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Impaired mitochondrial dynamics and function in the pathogenesis of Parkinson's disease.
Exp Neurol. 2009 Aug; 218(2):235-46.EN

Abstract

Parkinson's disease (PD), the most frequent movement disorder, is caused by the progressive loss of the dopamine neurons within the substantia nigra pars compacta (SNc) and the associated deficiency of the neurotransmitter dopamine in the striatum. Most cases of PD occur sporadically with unknown cause, but mutations in several genes have been linked to genetic forms of PD (alpha-synuclein, Parkin, DJ-1, PINK1, and LRRK2). These genes have provided exciting new avenues to study PD pathogenesis and the mechanisms underlying the selective dopaminergic neuron death in PD. Epidemiological studies in humans, as well as molecular studies in toxin-induced and genetic animal models of PD show that mitochondrial dysfunction is a defect occurring early in the pathogenesis of both sporadic and familial PD. Mitochondrial dynamics (fission, fusion, migration) is important for neurotransmission, synaptic maintenance and neuronal survival. Recent studies have shown that PINK1 and Parkin play crucial roles in the regulation of mitochondrial dynamics and function. Mutations in DJ-1 and Parkin render animals more susceptible to oxidative stress and mitochondrial toxins implicated in sporadic PD, lending support to the hypothesis that some PD cases may be caused by gene-environmental factor interactions. A small proportion of alpha-synuclein is imported into mitochondria, where it accumulates in the brains of PD patients and may impair respiratory complex I activity. Accumulation of clonal, somatic mitochondrial DNA deletions has been observed in the substantia nigra during aging and in PD, suggesting that mitochondrial DNA mutations in some instances may pre-dispose to dopamine neuron death by impairing respiration. Besides compromising cellular energy production, mitochondrial dysfunction is associated with the generation of oxidative stress, and dysfunctional mitochondria more readily mediate the induction of apoptosis, especially in the face of cellular stress. Collectively, the studies examined and summarized here reveal an important causal role for mitochondrial dysfunction in PD pathogenesis, and suggest that drugs and genetic approaches with the ability to modulate mitochondrial dynamics, function and biogenesis may have important clinical applications in the future treatment of PD.

Authors+Show Affiliations

Department of Anatomy and Neurobiology, University of Kentucky, Lexington, 40536, USA. hansruedi.bueler@uky.edu

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

19303005

Citation

Büeler, Hansruedi. "Impaired Mitochondrial Dynamics and Function in the Pathogenesis of Parkinson's Disease." Experimental Neurology, vol. 218, no. 2, 2009, pp. 235-46.
Büeler H. Impaired mitochondrial dynamics and function in the pathogenesis of Parkinson's disease. Exp Neurol. 2009;218(2):235-46.
Büeler, H. (2009). Impaired mitochondrial dynamics and function in the pathogenesis of Parkinson's disease. Experimental Neurology, 218(2), 235-46. https://doi.org/10.1016/j.expneurol.2009.03.006
Büeler H. Impaired Mitochondrial Dynamics and Function in the Pathogenesis of Parkinson's Disease. Exp Neurol. 2009;218(2):235-46. PubMed PMID: 19303005.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Impaired mitochondrial dynamics and function in the pathogenesis of Parkinson's disease. A1 - Büeler,Hansruedi, Y1 - 2009/03/18/ PY - 2009/01/22/received PY - 2009/02/26/revised PY - 2009/03/03/accepted PY - 2009/3/24/entrez PY - 2009/3/24/pubmed PY - 2009/9/5/medline SP - 235 EP - 46 JF - Experimental neurology JO - Exp Neurol VL - 218 IS - 2 N2 - Parkinson's disease (PD), the most frequent movement disorder, is caused by the progressive loss of the dopamine neurons within the substantia nigra pars compacta (SNc) and the associated deficiency of the neurotransmitter dopamine in the striatum. Most cases of PD occur sporadically with unknown cause, but mutations in several genes have been linked to genetic forms of PD (alpha-synuclein, Parkin, DJ-1, PINK1, and LRRK2). These genes have provided exciting new avenues to study PD pathogenesis and the mechanisms underlying the selective dopaminergic neuron death in PD. Epidemiological studies in humans, as well as molecular studies in toxin-induced and genetic animal models of PD show that mitochondrial dysfunction is a defect occurring early in the pathogenesis of both sporadic and familial PD. Mitochondrial dynamics (fission, fusion, migration) is important for neurotransmission, synaptic maintenance and neuronal survival. Recent studies have shown that PINK1 and Parkin play crucial roles in the regulation of mitochondrial dynamics and function. Mutations in DJ-1 and Parkin render animals more susceptible to oxidative stress and mitochondrial toxins implicated in sporadic PD, lending support to the hypothesis that some PD cases may be caused by gene-environmental factor interactions. A small proportion of alpha-synuclein is imported into mitochondria, where it accumulates in the brains of PD patients and may impair respiratory complex I activity. Accumulation of clonal, somatic mitochondrial DNA deletions has been observed in the substantia nigra during aging and in PD, suggesting that mitochondrial DNA mutations in some instances may pre-dispose to dopamine neuron death by impairing respiration. Besides compromising cellular energy production, mitochondrial dysfunction is associated with the generation of oxidative stress, and dysfunctional mitochondria more readily mediate the induction of apoptosis, especially in the face of cellular stress. Collectively, the studies examined and summarized here reveal an important causal role for mitochondrial dysfunction in PD pathogenesis, and suggest that drugs and genetic approaches with the ability to modulate mitochondrial dynamics, function and biogenesis may have important clinical applications in the future treatment of PD. SN - 1090-2430 UR - https://www.unboundmedicine.com/medline/citation/19303005/Impaired_mitochondrial_dynamics_and_function_in_the_pathogenesis_of_Parkinson's_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-4886(09)00080-6 DB - PRIME DP - Unbound Medicine ER -