Mitochondrial dysfunction in genetic animal models of Parkinson's disease.
, Tsika E
, Moore DJ
Laboratory of Molecular Neurodegenerative Research, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
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Mitochondria are highly dynamic, multifunctional organelles. Aside from their major role in energy metabolism, they are also crucial for many cellular processes including neurotransmission, synaptic maintenance, calcium homeostasis, cell death, and neuronal survival. SIGNIFICANCE: Increasing evidence supports a role for abnormal mitochondrial function in the molecular pathophysiology of Parkinson's disease (PD). For three decades we have known that mitochondrial toxins are capable of producing clinical parkinsonism in humans. PD is the most common neurodegenerative movement disorder that is characterized by the progressive loss of substantia nigra dopaminergic neurons leading to a deficiency of striatal dopamine. Although the neuropathology underlying the disease is well defined, it remains unclear why nigral dopaminergic neurons degenerate and die. RECENT ADVANCES: Most PD cases are idiopathic, but there are rare familial cases. Mutations in five genes are known to unambiguously cause monogenic familial PD: α-synuclein, parkin, DJ-1, PTEN-induced kinase 1 (PINK1), and leucine-rich repeat kinase 2 (LRRK2). These key molecular players are proteins of seemingly diverse function, but with potentially important roles in mitochondrial maintenance and function. Cell and animal-based genetic models have provided indispensable tools for understanding the molecular basis of PD, and have provided additional evidence implicating mitochondrial dysfunction as a primary pathogenic pathway leading to the demise of dopaminergic neurons in PD. CRITICAL ISSUES: Here, we critically discuss the evidence for mitochondrial dysfunction in genetic animal models of PD, and evaluate whether abnormal mitochondrial function represents a cause or consequence of disease pathogenesis. FUTURE DIRECTIONS: Mitochondria may represent a potential target for the development of disease-modifying therapies.
PMID: 21848447 [PubMed - in process]