Defects of mitochondrial function have been identified in several neurodegenerative diseases. These include abnormalities induced by mutations of mitochondrial DNA (mtDNA) those caused by mutation of nuclear genes encoding mitochondrial proteins, and in some cases, exposure to mitochondrial toxins.
MtDNA mutation are associated with a variety of progressive encephalomyopathies inn which there is evidence of neurodegeneration. These include Kearns-Sayre syndrome myopathy, encephalopathy, lactic acidosis and stroke – like episodes (MELAS) and Myoclonic epilepsy with ragged red fibers (MERRF) and Leigh’s syndrome. In Leber’s heredity optic neuropathy (LHON), there is degeneration of retinal ganglion cells. Occasional reports have described mtDNA mutation in association with Parkinson’s Diseases (PD) and amyotrophic lateral sclerosis (ALS).
Mutation in the nuclear gene for mtDNA polymerase gamma (POLG) have been found in a range of disorders that include Alper’s Syndrome, progressive external opthalmoplegia (PEO), sensory ataxia, neuropathy, dysarthria and ophthalmoplegia (SANDO) and parkinsonism. Although most cases of Parkinsonism due to POLG mutations have been preceded by PEO, some have been described with only Parkinsonism and neuropathy. The early onset from hepatocerebral mtDNA depletion is associated with mutation in the deoxyguanosine kinase gene and thymidine phosphorylase mutation are a cause of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Mutation have been identified in nuclear genes for mitochondrial protein involved in the assembly and maintenance of cytochrome oxidase including SCO2, SURF1, COX10, COX15 and LRPPRC. These results in autosomal recessive COX deficiency that usually presents in early life with Leigh syndrome, myopathy and encephalopathy, lactic acidosis and a progressive course with early death.
There is deficiency in complex I activity in PD substantia nigra and platelets. Complex I is the target of toxin known to produce parkinsonian features in human e.g. MPTP and anonnacin, and animal model of PD e.g. rotenone and tetrahydroisoquinoline. The pathogenesis of PD also includes protein aggregation (Lewy bodies). Mitochondrial dysfunction will contribute to dysfunction of the energy dependent ubiquitin proteasomal system (UPS) and oxidative stress will add to the substrate load. Several of the single gene mutation causing familial PD has been identified as mitochondrial proteins including PINK1, DJ1 and parkin. The cellular disruption of the latter appears to depend upon the stage of cell differentiation. A proportion of LRRK2 is associated with the outer mitochondrial membrane.
Mitochondrial dysfunction has also been identifies in AD, ALS and Huntington’s diseases although the relationship to pathogenesis in the respective diseases remain unknown.
McFarland R, Taylor RW, & Turnbull DM (2010). A neurological perspective on mitochondrial disease. Lancet neurology, 9 (8), 829-40 PMID: 20650404
Venna N (2004). Mitochondrial neurological diseases: a clinician’s perspective. Neurology India, 52 (3), 305-6 PMID: 15472416
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