Amyotrophic lateral sclerosis-associated mutant VAPBP56S perturbs calcium homeostasis to disrupt axonal transport of mitochondria

Mórotz, Gábor M.; Vos, Kurt J. De; Vagnoni, Alessio; Ackerley, Steven; Shaw, Christopher E.; Miller, Christopher C.J.

doi:10.1093/hmg/dds011

Cited by 119 publications

(95 citation statements)

References 56 publications

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“…Similar to recent findings in amyotrophic lateral sclerosis (45), mitochondria of PCs were abnormally condensed, resembling those undergoing mitophagy. PCs in the PC degeneration mouse, an ataxic mouse model, have shown accumulation of mitochondria undergoing mitophagy, similarly to findings in E280A-FAD (17).…”

Section: Figuresupporting

confidence: 89%

Familial Alzheimer’s disease–associated presenilin-1 alters cerebellar activity and calcium homeostasis

Sepulveda‐Falla¹,

Barrera-Ocampo²,

Hagel³

et al. 2014

J. Clin. Invest.

117

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Familial Alzheimer's disease (FAD) is characterized by autosomal dominant heritability and early disease onset. Mutations in the gene encoding presenilin-1 (PS1) are found in approximately 80% of cases of FAD, with some of these patients presenting cerebellar damage with amyloid plaques and ataxia with unclear pathophysiology. A Colombian kindred carrying the PS1-E280A mutation is the largest known cohort of PS1-FAD patients. Here, we investigated PS1-E280A-associated cerebellar dysfunction and found that it occurs early in PS1-E208A carriers, while cerebellar signs are highly prevalent in patients with dementia. Postmortem analysis of cerebella of PS1-E280A carrier revealed greater Purkinje cell (PC) loss and more abnormal mitochondria compared with controls. In PS1-E280A tissue, ER/mitochondria tethering was impaired, Ca 2+ channels IP3Rs and CACNA1A were downregulated, and Ca 2+ -dependent mitochondrial transport proteins MIRO1 and KIF5C were reduced. Accordingly, expression of PS1-E280A in a neuronal cell line altered ER/ mitochondria tethering and transport compared with that in cells expressing wild-type PS1. In a murine model of PS1-FAD, animals exhibited mild ataxia and reduced PC simple spike activity prior to cerebellar β-amyloid deposition. Our data suggest that impaired calcium homeostasis and mitochondrial dysfunction in PS1-FAD PCs reduces their activity and contributes to motor coordination deficits prior to Aβ aggregation and dementia. We propose that PS1-E280A affects both Ca 2+ homeostasis and Aβ precursor processing, leading to FAD and neurodegeneration.

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Section: Figuresupporting

confidence: 89%

Familial Alzheimer’s disease–associated presenilin-1 alters cerebellar activity and calcium homeostasis

Sepulveda‐Falla¹,

Barrera-Ocampo²,

Hagel³

et al. 2014

J. Clin. Invest.

117

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“…Altered mitochondrial transport was reported in fALS-linked hSOD1 G93A , TDP-43, and VAPB-P56S mice (Bilsland et al, 2010; De Vos et al, 2007; Magrané and Manfredi, 2009; Mórotz et al, 2012; Shan et al, 2010). Thus, one of current hypotheses is that the aberrant axonal accumulation of damaged mitochondria could be due to reduced mitochondrial transport.…”

Section: Introductionmentioning

confidence: 95%

Endolysosomal Deficits Augment Mitochondria Pathology in Spinal Motor Neurons of Asymptomatic fALS Mice

Xie

Zhou

Lin

et al. 2015

Neuron

140

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One pathological hallmark in ALS motor neurons (MNs) is axonal accumulation of damaged mitochondria. A fundamental question remains: does reduced degradation of those mitochondria by impaired autophagy-lysosomal system contribute to mitochondrial pathology? Here, we reveal MN-targeted progressive lysosomal deficits accompanied by impaired autophagic degradation beginning at asymptomatic stages in fALS-linked hSOD1G93A mice. Lysosomal deficits result in accumulation of autophagic vacuoles engulfing damaged mitochondria along MN axons. Live imaging of spinal MNs from the adult disease mice demonstrates impaired dynein-driven retrograde transport of late endosomes (LEs). Expressing dynein-adaptor snapin reverses transport defects by competing with hSOD1G93A for binding dynein, thus rescuing autophagy-lysosomal deficits, enhancing mitochondria turnover, improving MN survival, and ameliorating the disease phenotype in hSOD1G93A mice. Our study provides a new mechanistic link for hSOD1G93A-mediated impairment of LE transport to autophagy-lysosome deficits and mitochondria pathology. Understanding these early pathological events benefits development of new therapeutic interventions for fALS-linked MN degeneration.

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“…The Pro56Ser mutation in VAPB associated with ALS increases its affinity for PTPIP51, thereby enhancing calcium transfer into mitochondria (De Vos et al, 2012). Furthermore, ER calcium dysregulation in VAPB mutant neurons results in decreased mitochondrial transport, possibly because of the effects of calcium on Miro1, the cargo adaptor that connects mitochondria to kinesins and microtubules (Morotz et al, 2012). Interestingly, overexpression of wild type or ALS-linked mutants of TDP43 result in mislocalization of the protein in the cytosol and interferes with VAPB-PIPT51 interactions, thereby disrupting ER-mitochondrial contacts (Stoica et al, 2014).…”

Section: Mitochondria-er Interactions In Alsmentioning

confidence: 99%

Mitochondria and endoplasmic reticulum crosstalk in amyotrophic lateral sclerosis

Manfredi

Kawamata

2016

Neurobiology of Disease

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Physical and functional interactions between mitochondria and the endoplasmic reticulum (ER) are crucial for cell life. These two organelles are intimately connected and collaborate to essential processes, such as calcium homeostasis and phospholipid biosynthesis. The connections between mitochondria and endoplasmic reticulum occur through structures named mitochondria associated membranes (MAMs), which contain lipid rafts and a large number of proteins, many of which serve multiple functions at different cellular sites. Growing evidence strongly suggest that alterations of ER-mitochondria interactions are involved in neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), a devastating and rapidly fatal motor neuron disease. Mutations in proteins that participate in ER-mitochondria interactions and MAM functions are increasingly being associated with genetic forms of ALS and other neurodegenerative diseases. This evidence strongly suggests that, rather than considering the two organelles separately, a better understanding of the disease process can derive from studying the alterations in the their crosstalk. In this review we discuss normal and pathological ER-mitochondria interactions and the evidence that link them to ALS.

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Amyotrophic lateral sclerosis-associated mutant VAPBP56S perturbs calcium homeostasis to disrupt axonal transport of mitochondria

Cited by 119 publications

References 56 publications

Familial Alzheimer’s disease–associated presenilin-1 alters cerebellar activity and calcium homeostasis

Familial Alzheimer’s disease–associated presenilin-1 alters cerebellar activity and calcium homeostasis

Endolysosomal Deficits Augment Mitochondria Pathology in Spinal Motor Neurons of Asymptomatic fALS Mice

Mitochondria and endoplasmic reticulum crosstalk in amyotrophic lateral sclerosis

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