Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0040822 (tremor)
 18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mitochondrial m-AAA protease has a crucial role in axonal development and maintenance. Human mitochondria possess two m-AAA protease isoenzymes: a hetero-oligomeric complex, composed of paraplegin and AFG3L2 (Afg3 like 2), and a homo-oligomeric AFG3L2 complex. Loss of function of paraplegin (encoded by the SPG7 gene) causes hereditary spastic paraplegia, a disease characterized by retrograde degeneration of cortical motor axons. Spg7(-/-) mice show a late-onset degeneration of long spinal and peripheral axons with accumulation of abnormal mitochondria. In contrast, Afg3l2(Emv66/Emv66) mutant mice, lacking the AFG3L2 protein, are affected by a severe neuromuscular phenotype, due to defects in motor axon development. The role of the homo-oligomeric m-AAA protease and the extent of cooperation and redundancy between the two isoenzymes in adult neurons are still unclear. Here we report an early-onset severe neurological phenotype in Spg7(-/-) Afg3l2(Emv66/+) mice, characterized by loss of balance, tremor and ataxia. Spg7(-/-) Afg3l2(Emv66/+) mice display acceleration and worsening of the axonopathy observed in paraplegin-deficient mice. In addition, they show prominent cerebellar degeneration with loss of Purkinje cells and parallel fibers, and reactive astrogliosis. Mitochondria from affected tissues are prone to lose mt-DNA and have unstable respiratory complexes. At late stages, neurons contain structural abnormal mitochondria defective in COX-SDH reaction. Our data demonstrate genetic interaction between the m-AAA isoenzymes and suggest that different neuronal populations have variable thresholds of susceptibility to reduced levels of the m-AAA protease. Moreover, they implicate impaired mitochondrial proteolysis as a novel pathway in cerebellar degeneration.
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PMID:Genetic interaction between the m-AAA protease isoenzymes reveals novel roles in cerebellar degeneration. 1928 3

Mitochondrial diseases (MIDs) are a large group of heterogeneous disorders due to mutations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) genes, the latter encoding proteins involved in mitochondrial function. A multisystem clinical picture that involves several organs, including both the peripheral and central nervous systems, is a common presentation of MID. Movement disorders, even isolated ones, are not rare. Cerebellar ataxia is common in myoclonic epilepsy with ragged red fibers (MERFF) due to mutations in the mitochondrial transfer RNA (tRNA) lysine gene, in Kearns-Sayre syndrome due to mtDNA deletions, in sensory ataxic neuropathy with dysarthria and ophthalmoplegia (SANDO) due to nuclear POLG1 gene mutations, and also in ARCA2, Friedreich's ataxia, SPG7, SCA28 and autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) due to mutations in nuclear genes involved in mitochondrial morphology or function. Myoclonus is a key feature of MERFF, but may also be encountered in mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), ARCA2, POLG1 mutations and Leigh syndrome. Dystonia is common in Leigh syndrome (which may be caused by 75 different genes) and in Leber hereditary ocular neuropathy (LHON) plus disease, due to mutations in mtDNA genes that encode subunits of NADH dehydrogenase, as well as in ARCA2, pantothenate kinase-associated neurodegeneration (PKAN), mitochondrial membrane protein-associated neurodegeneration (MPAN) and POLG1 mutations. Other movement disorders are rarer (such as parkinsonism, tremor, chorea). Although parkinsonism is more frequent in POLG1 mutations, and myoclonus in MERFF, most movement disorders are found either isolated or combined in numerous MIDs. The presence of associated neurological signs, whether central or peripheral, or of evocative magnetic resonance imaging (MRI) abnormalities (striatal necrosis) should prompt a search for MID. In cases of a particular clinical spectrum (LHON, MERFF, Kearns-Sayre, SANDO, SPG7, ARCA2, ARSACS), a search for the most frequently implicated mutation(s) is recommended. In other cases, muscle biopsies followed by metabolic and genetic studies may be useful for arriving at a diagnosis.
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PMID:Movement disorders in mitochondrial diseases. 2777 46