The mitochondrial permeability transition pore regulates Parkinson's disease development in mutant α-synuclein transgenic mice

Abstract

Parkinson’s disease (PD) is a movement disorder caused by neurodegeneration in neocortex, substantia nigra (SN) and brainstem and synucleinopathy. Some inherited PD is caused by mutations in α-synuclein (αSyn), and inherited and idiopathic PD are associated with mitochondrial perturbations. However, the mechanisms of pathogenesis are unresolved. We characterized a human αSyn transgenic mouse model and tested the hypothesis that the mitochondrial permeability transition pore (mPTP) is involved in the disease mechanisms. C57BL/6 mice expressing human A53T-mutant αSyn driven by a Thy1 promoter develop a severe, age-related, fatal movement disorder involving ataxia, rigidity, and postural instability. These mice develop synucleinopathy and neocortical, SN, and cerebello-rubro-thalamic degeneration involving mitochondriopathy and apoptotic and non-apoptotic neurodegeneration. Interneurons undergo apoptotic degeneration in young mice. Mutant αSyn associated with dysmorphic neuronal mitochondria and bound voltage-dependent anion channels. Genetic ablation of cyclophilin D, an mPTP modulator, delayed disease onset and extended lifespans of mutant αSyn mice. Thus, mutant αSyn transgenic mice on a C57BL/6 background develop PD-like phenotypes, and the mPTP is involved in their disease mechanisms.

MicroRNA-7 Regulates the Function of Mitochondrial Permeability Transition Pore by Targeting VDAC1 Expression

“…Interestingly, human ␣-synuclein was found to associate with VDAC1 in the brain stem, striatum, and cortex of transgenic mice expressing a pathogenic mutant form (A53T) of human ␣-synuclein (10). The mitochondria associated with human ␣-synuclein A53T appeared to be swollen, an indication of opening of the mitochondrial PTP (10). This finding suggests that increased level of ␣-synuclein in vivo could play a role in opening the mitochondrial PTP.…”

Soluble, Prefibrillar α-Synuclein Oligomers Promote Complex I-dependent, Ca2+-induced Mitochondrial Dysfunction

“…Although the role of mitochondrial permeability transition in PD-related cell death requires further study, two recent reports support the in vivo relevance of our data. Findings from Martin et al (32) indicate that the genetic ablation of cyclophilin D, the mPTP modulator and target of CsA, delayed the onset of mitochondrial abnormalities and neuronal apoptosis in Thy1-␣Syn A53T transgenic mice. Also, Büttner et al (33) showed that overexpression of ␣Syn in yeast led to cell death and a redistribution of the proapoptotic nuclease EndoG from mitochondria to the nucleus, and these effects could both be rescued by genetic modulation of the mPTP components.…”

“…␣Syn may associate abnormally with mitochondria in PD patients and animal models (27)(28)(29)(30)(31)(32)(33). An apparent partial subcellular redistribution of ␣Syn from the cytoplasm to the inner and outer mitochondrial membranes (27,34,35) is correlated with mitochondrial dysfunction, including increased oxidative stress, reduced mitochondrial membrane potential (⌬⌿ m ), altered Ca 2ϩ homeostasis, and cytochrome c release (27, 29 -31, 33, 36, 37).…”

Mitochondria and aging: A role for the mitochondrial transition pore?

“…Indeed, CypD deletion studies show benefit in mouse models of amyloid lateral sclerosis and Parkinson's diseases as genetic ablation of CypD delayed the onset of disease and extended lifespan (Martin, Semenkow, Hanaford, & Wong, 2014; Martin et al., 2009), strengthening the role of the mPTP in the mechanisms of both diseases. The beneficial effect observed with a novel small mPTP inhibitor in a mouse model of amyloid lateral sclerosis confirmed that the mPTP could represent an interesting target for drug development in amyloid lateral sclerosis (Martin, Fancelli, et al., 2014).…”