Abstract
Alterations in mitochondrial function and morphology are associated with many human diseases, including cancer and neurodegenerative diseases. Mitochondrial impairment is linked to Parkinson’s disease (PD) pathogenesis, and alterations in mitochondrial dynamics are seen in PD models. In particular, α-synuclein (αS) abnormalities are often associated with pathological changes to mitochondria. However, the relationship between αS pathology and mitochondrial dynamics remains poorly defined. Herein, we examined a mouse model of α-synucleinopathy for αS pathology-linked alterations in mitochondrial dynamics in vivo. We show that α-synucleinopathy in a transgenic (Tg) mouse model expressing familial PD-linked mutant A53T human αS (TgA53T) is associated with a decrease in Drp1 localization and activity in the mitochondria. In addition, we show that the loss of Drp1 function in the mitochondria is associated with two distinct phenotypes of enlarged neuronal mitochondria. Mitochondrial enlargement was only present in diseased animals and, apart from Drp1, other proteins involved in mitochondrial dynamics are unlikely to cause these changes, as their levels remained mostly unchanged. Further, the levels of Mfn1, a protein that facilitates mitochondrial fusion, was decreased nonspecifically with transgene expression. These results support the view that altered mitochondrial dynamics are a significant neuropathological factor in α-synucleinopathies.
Highlights
IntroductionThe current view is that abnormalities in α-synuclein (αS), the structural component of Lewy bodies (LBs) and Lewy neurites (LNs) [3], are mechanistically linked to neurodegeneration in Parkinson’s disease (PD)
Parkinson’s disease (PD) is the second-most common neurodegenerative disease of the central nervous system, and affects about 1% of the population over the age of 60 [1].PD is characterized by the presence of proteinaceous aggregates called Lewy bodies (LBs) and Lewy neurites (LNs) in brain tissue, and a severe loss of dopaminergic neurons in the substantia nigra pars compacta [2].The current view is that abnormalities in α-synuclein, the structural component of LBs and LNs [3], are mechanistically linked to neurodegeneration in PD
Dynamin-related protein 1 (Drp1) is a Guanosin-50 -Triphosphatase (GTPase) of the Dynamin family that is mainly localized throughout the cytosol in the dense puncta, but is translocated to the mitochondrial outer membrane to promote mitochondrial fission [38,39]
Summary
The current view is that abnormalities in α-synuclein (αS), the structural component of LBs and LNs [3], are mechanistically linked to neurodegeneration in PD. This view is supported by the fact that while a majority (~85%) of PD cases are considered idiopathic [1], missense mutations or gene multiplication in the SNCA gene, which encodes αS, cause highly penetrant, autosomal-dominant familial PD in humans [4]. The expression of mutant human αS in transgenic (Tg) animals causes progressive neurodegeneration that is associated with αS aggregation [5,6].
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