The Neurodegenerative Disease Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS): Cellular Defects Due To Loss of Sacsin Function
Abstract
Sacsin, which is mutated in the neurodegenerative disease Autosomal Recessive Spastic
Ataxia of Charlevoix-Saguenay (ARSACS), is a 520 kDa modular protein with regions
of homology to molecular chaperones and domains linking to the ubiquitin proteasome
system. This suggests a role in proteostasis.
Previously, sacsin has been shown to partially localise with mitochondria, and loss of
sacsin results in elongated and dysfunctional mitochondria. Moreover, alterations in
neurofilaments have recently been reported in a mouse model of ARSACS. Despite
these findings, pathophysiological mechanisms of ARSACS are poorly understood.
The aim of this thesis was to elucidate the cellular role of sacsin by determining how
loss of its function leads to the observed mitochondrial and intermediate filament
defects. This hoped to shed light on the mechanism of disease in ARSACS.
The results indicate that the mitochondrial elongation seen in ARSACS is likely due to
reduced mitochondrial localisation of the essential fission factor DRP1. This may be
mediated by loss of function of a complex involving sacsin and dynactin-6, a subunit of
the dynein-dynactin motor complex, which has previously been shown to be required
for DRP1 mitochondrial recruitment. DRP1-mediated mitochondrial fission is necessary
for mitochondrial quality control; hence a disruption to mitochondrial quality control is
likely to occur in sacsin deficient cells, which may explain the mitochondrial
dysfunction in ARSACS.
Furthermore, sacsin null cells display a dramatic collapse and perinuclear bundling of
the vimentin intermediate filament network. This is coupled with the displacement of
cellular organelles, particularly mitochondria, early endosomes and the Golgi, which
accumulate at the periphery of the vimentin bundle. These are characteristic features of
aggresome formation, indicating an aggregation of misfolded protein, which occurs due
to disrupted proteostasis. Further supporting this, the proteostasis components ubiquitin,
HSP70, LAMP2 and p62 are recruited to the perinuclear vimentin bundles.
In summary, the findings of this thesis indicate a role for sacsin in mitochondrial and
protein quality control, the dysfunction of which is likely to be particularly detrimental
in neurons. Mitochondrial dysfunction along with protein misfolding and aggregation
are implicated in many neurodegenerative diseases, and ARSACS is no exception.
Authors
Duncan, Emma JaneCollections
- Theses [4223]