bims-midneu Biomed News
on Mitochondrial dysfunction in neurodegeneration
Issue of 2021‒06‒27
fourteen papers selected by
Radha Desai
Merck Sharp & Dohme Corp.
  1. Loss of neuronal Miro1 disrupts mitophagy and induces hyperactivation of the integrated stress response.
  2. Mitochondrial-derived vesicles compensate for loss of LC3-mediated mitophagy.
  3. Mitochondrial Ca2+ oscillation induces mitophagy initiation through the PINK1-Parkin pathway.
  4. Mitophagy in Cerebral Ischemia and Ischemia/Reperfusion Injury.
  5. Krüppel-Like Factor 6 Silencing Prevents Oxidative Stress and Neurological Dysfunction Following Intracerebral Hemorrhage via Sirtuin 5/Nrf2/HO-1 Axis.
  6. High intensity interval training induces dysregulation of mitochondrial respiratory complex and mitophagy in the hippocampus of middle-aged mice.
  7. Amyloid-β Protein Precursor Deficiency Changes Neuronal Electrical Activity and Levels of Mitochondrial Proteins in the Medial Prefrontal Cortex.
  8. Coordinated pyruvate kinase activity is crucial for metabolic adaptation and cell survival during mitochondrial dysfunction.
  9. R13 preserves motor performance in SOD1G93A mice by improving mitochondrial function.
  10. Mitochondrial STAT5A promotes metabolic remodeling and the Warburg effect by inactivating the pyruvate dehydrogenase complex.
  11. Brain energy metabolism and neurodegeneration: hints from CSF lactate levels in dementias.
  12. Lycopene prevents oxygen-glucose deprivation-induced autophagic death in SH-SY5Y cells via inhibition of the oxidative stress-activated AMPK/mTOR pathway.
  13. Gene Therapy for Parkinson's Disease Associated with GBA1 Mutations.
  14. Blood Mitochondrial DNA Copy Number: What Are We Counting?
  1. EMBO J. 2021 Jun 21. e100715
    Loss of neuronal Miro1 disrupts mitophagy and induces hyperactivation of the integrated stress response.
    Guillermo López-Doménech, Jack H Howden, Christian Covill-Cooke, Corinne Morfill, Jigna V Patel, Roland Bürli, Damian Crowther, Nicol Birsa, Nicholas J Brandon, Josef T Kittler.
      Clearance of mitochondria following damage is critical for neuronal homeostasis. Here, we investigate the role of Miro proteins in mitochondrial turnover by the PINK1/Parkin mitochondrial quality control system in vitro and in vivo. We find that upon mitochondrial damage, Miro is promiscuously ubiquitinated on multiple lysine residues. Genetic deletion of Miro or block of Miro1 ubiquitination and subsequent degradation lead to delayed translocation of the E3 ubiquitin ligase Parkin onto damaged mitochondria and reduced mitochondrial clearance in both fibroblasts and cultured neurons. Disrupted mitophagy in vivo, upon post-natal knockout of Miro1 in hippocampus and cortex, leads to a dramatic increase in mitofusin levels, the appearance of enlarged and hyperfused mitochondria and hyperactivation of the integrated stress response (ISR). Altogether, our results provide new insights into the central role of Miro1 in the regulation of mitochondrial homeostasis and further implicate Miro1 dysfunction in the pathogenesis of human neurodegenerative disease.
    Keywords:  Parkinson’s disease; Rhot1; Rhot2; eIF2α; megamitochondria
    DOI:  https://doi.org/10.15252/embj.2018100715
  2. Dev Cell. 2021 Jun 24. pii: S1534-5807(21)00481-0. [Epub ahead of print]
    Mitochondrial-derived vesicles compensate for loss of LC3-mediated mitophagy.
    Christina G Towers, Darya K Wodetzki, Jacqueline Thorburn, Katharine R Smith, M Cecilia Caino, Andrew Thorburn.
      Mitochondria are critical metabolic and signaling hubs, and dysregulated mitochondrial homeostasis is implicated in many diseases. Degradation of damaged mitochondria by selective GABARAP/LC3-dependent macro-autophagy (mitophagy) is critical for maintaining mitochondrial homeostasis. To identify alternate forms of mitochondrial quality control that functionally compensate if mitophagy is inactive, we selected for autophagy-dependent cancer cells that survived loss of LC3-dependent autophagosome formation caused by inactivation of ATG7 or RB1CC1/FIP200. We discovered rare surviving autophagy-deficient clones that adapted to maintain mitochondrial homeostasis after gene inactivation and identified two enhanced mechanisms affecting mitochondria including mitochondrial dynamics and mitochondrial-derived vesicles (MDVs). To further understand these mechanisms, we quantified MDVs via flow cytometry and confirmed an SNX9-mediated mechanism necessary for flux of MDVs to lysosomes. We show that the autophagy-dependent cells acquire unique dependencies on these processes, indicating that these alternate forms of mitochondrial homeostasis compensate for loss of autophagy to maintain mitochondrial health.
    Keywords:  ATG7; FIP200; SNX9; autophagy; cancer; late endosomes; mitochondria; mitochondrial dynamics; mitochondrial-derived vesicles; mitophagy
    DOI:  https://doi.org/10.1016/j.devcel.2021.06.003
  3. Cell Death Dis. 2021 Jun 19. 12(7): 632
    Mitochondrial Ca2+ oscillation induces mitophagy initiation through the PINK1-Parkin pathway.
    Zhengying Yu, Haipeng Wang, Wanyi Tang, Shaoyang Wang, Xiaoying Tian, Yujie Zhu, Hao He.
      Dysregulation of the PINK1/Parkin-mediated mitophagy is essential to Parkinson's disease. Although important progress has been made in previous researches, the biochemical reagents that induce global and significant mitochondrial damage may still hinder deeper insights into the mechanisms of mitophagy. The origin of PINK1/Parkin pathway activation in mitophagy remains elusive. In this study, we develop an optical method, ultra-precise laser stimulation (UPLaS) that delivers a precise and noninvasive stimulation onto a submicron region in a single mitochondrial tubular structure. UPLaS excites localized mitochondrial Ca2+ (mitoCa2+) oscillations with tiny perturbation to mitochondrial membrane potential (MMP) or mitochondrial reactive oxygen species. The UPLaS-induced mitoCa2+ oscillations can directly induce PINK1 accumulation and Parkin recruitment on mitochondria. The Parkin recruitment by UPLaS requires PINK1. Our results provide a precise and noninvasive technology for research on mitophagy, which stimulates target mitochondria with little damage, and reveal mitoCa2+ oscillation directly initiates the PINK1-Parkin pathway for mitophagy without MMP depolarization.
    DOI:  https://doi.org/10.1038/s41419-021-03913-3
  4. Front Aging Neurosci. 2021 ;13 687246
    Mitophagy in Cerebral Ischemia and Ischemia/Reperfusion Injury.
    Luoan Shen, Qinyi Gan, Youcheng Yang, Cesar Reis, Zheng Zhang, Shanshan Xu, Tongyu Zhang, Chengmei Sun.
      Ischemic stroke is a severe cerebrovascular disease with high mortality and morbidity. In recent years, reperfusion treatments based on thrombolytic and thrombectomy are major managements for ischemic stroke patients, and the recanalization time window has been extended to over 24 h. However, with the extension of the time window, the risk of ischemia/reperfusion (I/R) injury following reperfusion therapy becomes a big challenge for patient outcomes. I/R injury leads to neuronal death due to the imbalance in metabolic supply and demand, which is usually related to mitochondrial dysfunction. Mitophagy is a type of selective autophagy referring to the process of specific autophagic elimination of damaged or dysfunctional mitochondria to prevent the generation of excessive reactive oxygen species (ROS) and the subsequent cell death. Recent advances have implicated the protective role of mitophagy in cerebral ischemia is mainly associated with its neuroprotective effects in I/R injury. This review discusses the involvement of mitochondria dynamics and mitophagy in the pathophysiology of ischemic stroke and I/R injury in particular, focusing on the therapeutic potential of mitophagy regulation and the possibility of using mitophagy-related interventions as an adjunctive approach for neuroprotective time window extension after ischemic stroke.
    Keywords:  ischemia/reperfusion injury (I/R injury); ischemic stroke; mitochondrial dysfunction; mitophagy; recanalization therapy; therapeutic window
    DOI:  https://doi.org/10.3389/fnagi.2021.687246
  5. Front Aging Neurosci. 2021 ;13 646729
    Krüppel-Like Factor 6 Silencing Prevents Oxidative Stress and Neurological Dysfunction Following Intracerebral Hemorrhage via Sirtuin 5/Nrf2/HO-1 Axis.
    Jia Sun, Jinzhong Cai, Junhui Chen, Siqiaozhi Li, Xin Liao, Yixuan He, Xudong Chen, Sean Hu.
      As a severe neurological deficit, intracerebral hemorrhage (ICH) is associated with overwhelming mortality. Subsequent oxidative stress and neurological dysfunction are likely to cause secondary brain injury. Therefore, this study sought to define the role of Krüppel-like factor 6 (KLF6) and underlying mechanism in oxidative stress and neurological dysfunction following ICH. An in vivo model of ICH was established in rats by injection of autologous blood, and an in vitro ICH cell model was developed in hippocampal neurons by oxyhemoglobin (OxyHb) exposure. Next, gain- and loss-of-function assays were performed in vivo and in vitro to clarify the effect of KLF6 on neurological dysfunction and oxidative stress in ICH rats and neuronal apoptosis and mitochondrial reactive oxygen species in OxyHb-induced hippocampal neurons. KLF6, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase 1 (HO-1) were highly expressed in hippocampal tissues of ICH rats, whereas sirtuin 5 (SIRT5) presented a poor expression. Mechanistically, KLF6 bound to the SIRT5 promoter and transcriptionally repressed SIRT5 to activate the Nrf2/HO-1 signaling pathway. KLF6 silencing alleviated neurological dysfunction and oxidative stress in ICH rats and diminished oxidative stress and neuronal apoptosis in OxyHb-induced neurons, whereas SIRT5 overexpression negated its effect. To sum up, KLF6 silencing elevated SIRT5 expression to inactivate the Nrf2/HO-1 signaling pathway, thus attenuating oxidative stress and neurological dysfunction after ICH.
    Keywords:  HO-1; Krüppel like factor 6; Nrf2; intracerebral hemorrhage; nerve injury; nuclear transcription factor; oxidative stress; sirtuin 5
    DOI:  https://doi.org/10.3389/fnagi.2021.646729
  6. Behav Brain Res. 2021 Jun 17. pii: S0166-4328(21)00272-2. [Epub ahead of print] 113384
    High intensity interval training induces dysregulation of mitochondrial respiratory complex and mitophagy in the hippocampus of middle-aged mice.
    Yu Zhang, Bo Liao, Shuai Hu, Shan-Yao Pan, Gui-Ping Wang, Yu-Long Wang, Zheng-Hong Qin, Li Luo.
      Autophagy is involved in aging-related cognitive impairment. Aerobic exercise training can improve cognitive function in the elderly and this effect may be associated with autophagic mechanisms and mitochondrial respiratory function. High intensity interval training (HIIT) has beneficial effects on heart and skeletal muscles by activating autophagy and/or mitophagy, but the effects of HIIT on autophagy/mitophagy in the aging brain are unknown. This study investigated the effects of HIIT on the mitochondrial respiratory complex and autophagy/mitophagy, and its relation to brain function. Thirteen middle-aged male ICR mice underwent HIIT for 7 weeks. The exercise program reduced the spontaneous behavior and exploration activities of the mice. The phosphorylation level of cAMP response element binding protein (CREB) and the protein expression of brain-derived neurotrophic factor (BDNF) decreased after the 7-week HIIT. Exercise downregulated the protein expression of Complex Ⅰ and upregulated the protein expression of Complex Ⅲ, Complex Ⅳ and Complex Ⅴ. HIIT also decreased the expression of mitophagy-related proteins in the mitochondrial fractions of the hippocampus. However, HIIT did not change the expression of autophagy-related proteins LC3, P62, Atg5, Atg7, Beclin-1 and Lamp2 in the total lysate of the hippocampus. These data indicated that HIIT might have negative effects on the plasticity of the hippocampus in middle-aged mice. The effects may be related to the dysregulation of CREB-BDNF signaling, mitochondrial respiratory complex and mitophagy induced by HIIT.
    Keywords:  Autophagy; High intensity interval training; Hippocampus; Mitochondrial respiratory complex; Mitophagy
    DOI:  https://doi.org/10.1016/j.bbr.2021.113384
  7. J Alzheimers Dis. 2021 ;81(4): 1469-1482
    Amyloid-β Protein Precursor Deficiency Changes Neuronal Electrical Activity and Levels of Mitochondrial Proteins in the Medial Prefrontal Cortex.
    Qingwei Huo, Sidra Tabassum, Ming Chen, Mengyao Sun, Yueming Deng, Xingzhi Zheng, Yi Li, Jian Chen, Cheng Long, Li Yang.
      BACKGROUND: Neuropathological features of Alzheimer's disease are characterized by the deposition of amyloid-β (Aβ) plaques and impairments in synaptic activity and memory. However, we know little about the physiological role of amyloid-β protein precursor (AβPP) from which Aβ derives.OBJECTIVE: Evaluate APP deficiency induced alterations in neuronal electrical activity and mitochondrial protein expression.
    METHODS: Utilizing electrophysiological, biochemical, pharmacological, and behavioral tests, we revealed aberrant local field potential (LFP), extracellular neuronal firing and levels of mitochondrial proteins.
    RESULT: We show that APP knockout (APP-/-) leads to increased gamma oscillations in the medial prefrontal cortex (mPFC) at 1-2 months old, which can be restored by baclofen (Bac), a γ-aminobutyric acid type B receptor (GABABR) agonist. A higher dose and longer exposure time is required for Bac to suppress neuronal firing in APP-/- mice than in wild type animals, indicating enhanced GABABR mediated activity in the mPFC of APP-/- mice. In line with increased GABABR function, the glutamine synthetase inhibitor, L-methionine sulfonate, significantly increases GABABR levels in the mPFC of APP-/- mice and this is associated with a significantly lower incidence of death. The results suggest that APP-/- mice developed stronger GABABR mediated inhibition. Using HEK 293 as an expression system, we uncover that AβPP functions to suppress GABABR expression. Furthermore, APP-/- mice show abnormal expression of several mitochondrial proteins.
    CONCLUSION: APP deficiency leads to both abnormal network activity involving defected GABABR and mitochondrial dysfunction, suggesting critical role of AβPP in synaptic and network function.
    Keywords:  Amyloid-β precursor protein; GABABR; L-methionine sulfonate; gamma oscillations; medial prefrontal cortex; mitochondria; spikes
    DOI:  https://doi.org/10.3233/JAD-201557
  8. Hum Mol Genet. 2021 Jun 24. pii: ddab168. [Epub ahead of print]
    Coordinated pyruvate kinase activity is crucial for metabolic adaptation and cell survival during mitochondrial dysfunction.
    Xiaoshan Zhou, Flora Mikaeloff, Sophie Curbo, Qian Zhao, Raoul V Kuiper, Ákos Végvári, Ujjwal Neogi, Anna Karlsson.
      Deoxyguanosine kinase (DGUOK) deficiency causes mtDNA depletion and mitochondrial dysfunction. We reported long survival of DGUOK knockout (Dguok-/-) mice despite low (<5%) mtDNA content in liver tissue. However, the molecular mechanisms enabling the extended survival remain unknown. Using transcriptomics, proteomics and metabolomics followed by in vitro assays, we aimed to identify the molecular pathways involved in the extended survival of the Dguok-/- mice. At the early stage, the serine synthesis and folate cycle were activated but declined later. Increased activity of the mitochondrial citric acid cycle (TCA cycle) and the urea cycle and degradation of branched chain amino acids were hallmarks of the extended lifespan in DGUOK deficiency. Furthermore, the increased synthesis of TCA cycle intermediates was supported by coordination of two pyruvate kinase genes, PKLR and PKM, indicating a central coordinating role of pyruvate kinases to support the long-term survival in mitochondrial dysfunction.
    DOI:  https://doi.org/10.1093/hmg/ddab168
  9. Theranostics. 2021 ;11(15): 7294-7307
    R13 preserves motor performance in SOD1G93A mice by improving mitochondrial function.
    Xiao Li, Chongyang Chen, Xu Zhan, Binyao Li, Zaijun Zhang, Shupeng Li, Yongmei Xie, Xiangrong Song, Yuanyuan Shen, Jianjun Liu, Ping Liu, Gong-Ping Liu, Xifei Yang.
      Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by death of motor neurons in the brain and spinal cord. However, so far, there is no effective treatment for ALS. Methods: In this study, R13, a prodrug of 7,8-dihydroxyflavone, selectively activating tyrosine kinase receptor B (TrkB) signaling pathway, was administered prophylactically to 40-day old SOD1G93A mice for 90 days. The motor performance was investigated by rotarod test, climbing-pole test, grip strength test and hanging endurance test. Afterwards, the spinal cord and medulla oblongata of 130-day old mice were harvested, and the proteomics revealed the effect of R13 on mouse protein expression profile. Astrocytes and microglial proliferation were assessed by immunohistochemical analysis. The number of motor neurons in the spinal cord is determined by Nissl staining. The effect of R13 on gastrocnemius morphology was assessed by HE staining. The effect of R13 on the survival rate was accomplished with worms stably expressing G93A SOD1. Results: Behavioral tests showed that R13 significantly attenuated abnormal motor performance of SOD1G93A mice. R13 reduced the advance of spinal motor neuron pathology and gastrocnemius muscle atrophy. The proliferation of microglia and astrocytes was reduced by R13 treatment. Mitochondriomics analysis revealed that R13 modified the mitochondrial protein expression profiles in the medulla oblongata and spinal cord of SOD1G93A mice, particularly promoting the expression of proteins related to oxidative phosphorylation (OXPHOS). Further study found that R13 activated AMPK/PGC-1α/Nrf1/Tfam, promoted mitochondrial biogenesis and ameliorated mitochondrial dysfunction. Lastly, R13 prolonged the survival rate of worms stably expressing G93A SOD1. Conclusions: These findings suggest oral R13 treatment slowed the advance of motor system disease in a reliable animal model of ALS, supporting that R13 might be useful for treating ALS.
    Keywords:  7,8-dihydroxyflavone; Amyotrophic lateral sclerosis; Mitochondria; Mitochondriomics; Motor performance
    DOI:  https://doi.org/10.7150/thno.56070
  10. Cell Death Dis. 2021 Jun 19. 12(7): 634
    Mitochondrial STAT5A promotes metabolic remodeling and the Warburg effect by inactivating the pyruvate dehydrogenase complex.
    Liang Zhang, Jianong Zhang, Yan Liu, Pingzhao Zhang, Ji Nie, Rui Zhao, Qin Shi, Huiru Sun, Dongyue Jiao, Yingji Chen, Xiaying Zhao, Yan Huang, Yao Li, Jian-Yuan Zhao, Wei Xu, Shi-Min Zhao, Chenji Wang.
      Signal transducer and activator 5a (STAT5A) is a classical transcription factor that plays pivotal roles in various biological processes, including tumor initiation and progression. A fraction of STAT5A is localized in the mitochondria, but the biological functions of mitochondrial STAT5A remain obscure. Here, we show that STAT5A interacts with pyruvate dehydrogenase complex (PDC), a mitochondrial gatekeeper enzyme connecting two key metabolic pathways, glycolysis and the tricarboxylic acid cycle. Mitochondrial STAT5A disrupts PDC integrity, thereby inhibiting PDC activity and remodeling cellular glycolysis and oxidative phosphorylation. Mitochondrial translocation of STAT5A is increased under hypoxic conditions. This strengthens the Warburg effect in cancer cells and promotes in vitro cell growth under hypoxia and in vivo tumor growth. Our findings indicate distinct pro-oncogenic roles of STAT5A in energy metabolism, which is different from its classical function as a transcription factor.
    DOI:  https://doi.org/10.1038/s41419-021-03908-0
  11. Neurobiol Aging. 2021 May 29. pii: S0197-4580(21)00172-X. [Epub ahead of print]105 333-339
    Brain energy metabolism and neurodegeneration: hints from CSF lactate levels in dementias.
    Chiara Giuseppina Bonomi, Vincenzo De Lucia, Alfredo Paolo Mascolo, Martina Assogna, Caterina Motta, Eugenia Scaricamazza, Fabrizio Sallustio, Nicola Biagio Mercuri, Giacomo Koch, Alessandro Martorana.
      Mitochondrial dysfunction is pivotal in the development of neurodegenerative dementias, causing cellular death alongside disease-specific pathogenic cascades. Holding cerebrospinal fluid (CSF) lactates as an indirect measure of brain metabolic activity, we first compared CSF lactate levels from patients with Alzheimer's disease (AD)-stratified according to the ATN system and epsilon genotype-frontotemporal dementia (FTD) and dementia with Lewy body (DLB) to findings from healthy controls. With respect to controls, we detected lower CSF lactates in patients with AD and FTD but comparable levels in patients with DLB. Second, a correlation analysis between CSF lactates and biomarkers of neurodegeneration identified an inverse correlation between lactates and levels of t-tau and p-tau only in the Alzheimer's continuum. The reduction of CSF lactate correlates to the advent of tauopathy and cellular death in AD, implying that Aβ pathology alone is not sufficient to induce neuronal metabolic impairment. The metabolic impairment in FTD patients has a similar explanation, as it is likely due to fast neuronal degeneration in the disease. The absence of CSF lactate reduction in patients with DLB may be related to the prevalent subcortical localization of the pathology.
    Keywords:  Alzheimer's continuum; Biomarkers; CSF lactates; Metabolic impairment; Neurodegenerative dementias
    DOI:  https://doi.org/10.1016/j.neurobiolaging.2021.05.011
  12. Mol Med Rep. 2021 Aug;pii: 594. [Epub ahead of print]24(2):
    Lycopene prevents oxygen-glucose deprivation-induced autophagic death in SH-SY5Y cells via inhibition of the oxidative stress-activated AMPK/mTOR pathway.
    Tan Li, Yang Zhang, Yi Qi, He Liu.
      Lycopene has been reported to exert a protective effect on the brain against transient ischemia‑induced damage; however, whether it could regulate autophagic neuronal death remains elusive. The present study aimed to investigate the role of autophagy in the protective effects of lycopene against neuronal damage and its underlying mechanism. Oxygen‑glucose deprivation (OGD) was used to simulate neuronal ischemic injury in human SH‑SY5Y cells. Lactate dehydrogenase (LDH) release assay revealed that OGD induced SH‑SY5Y cell death. Western blotting demonstrated that OGD upregulated the expression levels of the autophagy marker proteins autophagy protein 5 (ATG5) and LC3II, but downregulated the autophagy substrate p62 in a time‑dependent manner. By contrast, OGD‑induced cell death was significantly inhibited by the autophagy inhibitors 3‑methyladenine or bafilomycin A1 or by knockdown of ATG5, indicating that OGD may induce autophagic death in SH‑SY5Y cells. Notably, lycopene was shown not only to prevent OGD‑induced SH‑SY5Y cell death, but was also able to effectively inhibit OGD‑induced upregulation of ATG5 and LC3II, and downregulation of p62 in a dose‑dependent manner. Mechanistically, it was suggested that lycopene inhibited OGD‑induced activation of the AMPK/mTOR pathway via attenuation of oxidative stress by maintaining the intracellular antioxidant glutathione (GSH). Furthermore, the inhibitory role of lycopene in GSH depletion was found to be associated with the prevention of OGD‑induced depletion of intracellular cysteine and downregulation of xCT. Collectively, the present study demonstrated that lycopene protected SH‑SY5Y cells against OGD‑induced autophagic death by inhibiting oxidative stress‑dependent activation of the AMPK/mTOR pathway.
    Keywords:  OGD; autophagy; lycopene; oxidative stress; xCT
    DOI:  https://doi.org/10.3892/mmr.2021.12233
  13. J Parkinsons Dis. 2021 Jun 14.
    Gene Therapy for Parkinson's Disease Associated with GBA1 Mutations.
    Asa Abeliovich, Franz Hefti, Jeffrey Sevigny.
      Human genetic studies as well as studies in animal models indicate that lysosomal dysfunction plays a key role in the pathogenesis of Parkinson's disease. Among the lysosomal genes involved, GBA1, has the largest impact on Parkinson's disease risk. Deficiency in the GBA1 encoded enzyme glucocerebrosidase (GCase) leads to the accumulation of the GCase glycolipid substrates glucosylceramide and glucosylsphingosine and ultimately results in toxicity and inflammation and negatively affect many aspects of Parkinson's disease, including disease risk, the severity of presentation, age of onset, and likelihood of progression to dementia. These findings support the view that re-establishing normal range levels of GCase expression and enzyme activity may reduce the progression of Parkinson's disease in patients carrying GBA1 mutations. Studies in mouse models indicate that PR001, a rAAV9 vector-based gene therapy designed to deliver a functional GBA1 gene to the brain, suggest that this therapeutic approach may slow or stop disease progression. PR001 is currently being evaluated in clinical trials with Parkinson's disease patients carrying GBA1 mutations.
    Keywords:  AAV9; GBA1; Gaucher; Gene therapy; glucocerebrosidase
    DOI:  https://doi.org/10.3233/JPD-212739
  14. Mitochondrion. 2021 Jun 19. pii: S1567-7249(21)00083-0. [Epub ahead of print]
    Blood Mitochondrial DNA Copy Number: What Are We Counting?
    Martin Picard.
      There is growing scientific interest to develop scalable biological measures that capture mitochondrial (dys)function. Mitochondria have their own genome, the mitochondrial DNA (mtDNA), and it has been proposed that the number of mtDNA copies per cell (mtDNA copy number; mtDNAcn) reflects mitochondrial health. The common availability of stored DNA material or existing DNA sequencing data, especially from blood and other easy-to-collect samples, has made its quantification a popular approach in clinical and epidemiological studies. However, the interpretation of mtDNAcn is not univocal, and either a reduction or elevation in mtDNAcn can indicate dysfunction. The major determinants of blood-derived mtDNAcn are the heterogeneous cell type composition of leukocytes and platelet abundance, which can change with time of day, aging, and with disease. Hematopoiesis as a likely driver of blood mtDNAcn. Here we discuss the rationale and available methods to quantify mtDNAcn, the influence of blood cell type variations, and consider important gaps in knowledge that need to be resolved to maximize the scientific output around the investigation of blood mtDNAcn in humans.
    Keywords:  White blood cells; biomarker; count; leukocytes; mitochondrial function; mitochondrial genome; mitochondrion
    DOI:  https://doi.org/10.1016/j.mito.2021.06.010
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