Mitochondrial dysfunction and Purkinje cell loss in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)

Abstract

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a childhood-onset neurological disease resulting from mutations in the SACS gene encoding sacsin, a 4,579-aa protein of unknown function. Originally identified as a founder disease in Québec, ARSACS is now recognized worldwide. Prominent features include pyramidal spasticity and cerebellar ataxia, but the underlying pathology and pathophysiological mechanisms are unknown. We have generated an animal model for ARSACS, sacsin knockout mice, that display agedependent neurodegeneration of cerebellar Purkinje cells. To explore the pathophysiological basis for this observation, we examined the cell biological properties of sacsin. We show that sacsin localizes to mitochondria in non-neuronal cells and primary neurons and that it interacts with dynamin-related protein 1, which participates in mitochondrial fission. Fibroblasts from ARSACS patients show a hyperfused mitochondrial network, consistent with defects in mitochondrial fission. Sacsin knockdown leads to an overly interconnected and functionally impaired mitochondrial network, and mitochondria accumulate in the soma and proximal dendrites of sacsin knockdown neurons. Disruption of mitochondrial transport into dendrites has been shown to lead to abnormal dendritic morphology, and we observe striking alterations in the organization of dendritic fields in the cerebellum of knockout mice that precedes Purkinje cell death. Our data identifies mitochondrial dysfunction/mislocalization as the likely cellular basis for ARSACS and indicates a role for sacsin in regulation of mitochondrial dynamics.

Mitochondrial dynamics in neuronal injury, development and plasticity

“…Sacsin localizes to mitochondria where it interacts with Drp1 and might be involved in the assembly of higher-order complexes containing the fission enzyme. Consistent with this notion, fibroblasts from ARSACS patients exhibit severe hyperfusion of the mitochondrial network, which is recapitulated by knockdown of sacsin in neurons (Girard et al, 2012). Additionally, fibroblasts from ARSACS patients and fibroblasts in which sacsin had been knocked down both show a decrease in the formation of Drp1 foci at mitochondria, suggesting that sacsin stabilizes active fission complexes at mitochondria (Bradshaw et al, 2016).…”

Assessment of Whole-Brain White Matter by DTI in Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

“…2 In addition to developmental abnormalities in the TPF and their mechanical effects on the CST, axonal degeneration and, more extensively, demyelination in cerebral WM may explain a wide range of neurologic abnormalities other than spasticity and the progressive nature of the disease. Recently, Girard et al 30 showed localization of sacsin to mitochondria and a cascade of detrimental effects resulting in neuronal cell death by loss of sacsin function in knockout mice. These authors further suggested the presence of some common pathophysiologic features between ARSACS and some other neurodegenerative diseases with mitochondrial impairment such as Alzheimer, Parkinson, and Huntington disease.…”

Mitochondrial impairments contribute to Spinocerebellar ataxia type 1 progression and can be ameliorated by the mitochondria-targeted antioxidant MitoQ

“…Therefore, it is not surprising that mitochondrial dysfunction and oxidative stress have been implicated in various NDs (Burte et al, 2015;Chaturvedi and Flint Beal, 2013;Karbowski and Neutzner, 2012), such as Alzheimer's disease (AD) (Friedland-Leuner et al, 2014;Simoncini et al, 2015), Parkinson's disease (PD) (Haelterman et al, 2014;Hang et al, 2015;Overk and Masliah, 2014;Ryan et al, 2015), Huntington's disease (HD) (Ayala-Pena, 2013;Guedes-Dias et al, 2015;Labbadia and Morimoto, 2013;Tsunemi and La Spada, 2012) and Amyotrophic lateral sclerosis (ALS) (Cozzolino et al, 2013;Duffy et al, 2011;Magrane and Manfredi, 2009). Importantly, in inherited recessive ataxias such as Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) or Friedreich's ataxia, mutations within mitochondriaassociated proteins are the most frequent cause underlying the development of these disease (Calabrese et al, 2005;Criscuolo et al, 2015;Girard et al, 2012). These observations are not unexpected considering that PCs are amongst the most active neurons in the central nervous system and have a high energy demand that makes them particularly susceptible to mitochondrial impairment or dysfunction (Zeviani et al, 2012).…”