What Do Genes In Autosomal Dominant Pd Tell Us About Pathogenesis

The cause and pathogenesis of PD are incompletely understood, but rare mutations in familial cases (Table 1) are beginning to unravel the variety of cellular processes involved in the accumulation of Lewy bodies and dopaminergic cell death. It is not possible to discuss this fully without reference to the genetic discoveries in autosomal recessive parkinsonism, which have occurred in parallel with the finding of dominant genes and are outside the scope of this article. The subject has been recently reviewed.[26,27] Derangements in protein handling seem to be central in the pathogenesis of PD (Fig. 1). a-Synuclein is a small protein characterized by imperfect repeats (KTKEGV) distributed through most its amino-terminal half of the polypeptide that also includes a hydrophobic middle region and an acidic carboxy-terminal region. Its function is not established but it is believed to modulate synaptic vesicle turnover and synaptic plasticity. In vitro, it polymerizes into ~ 10-nm fibrils, which are a major component of nigral Lewy bodies and Lewy neurites in PD and other forms of parkinsonism. It is unfolded in its native state but becomes structured on binding to lipid membranes. In the unfolded form, it is degraded by proteosomes in a ubiquitin-independent manner. In diseases where it aggregates, it forms a p-sheet structure. a-Synuclein promotes mitochondrial dysfunction and oxidative stress—another central aspect in the pathogenesis of PD.[28] Oxidative stress may further promote aggregation and lead to Lewy body formation. a-Synuclein knockout mice are pheno-typically normal and show no abnormalities of dopami-nergic function, and a-synuclein mutations are likely to be gain-of-function mutations rather than loss-of-function mutations. Although none of the transgenic animal models replicates all features of the human disease, they do show neurodegeneration associated with abnormal accumulation of detergent-insoluble a-synuclein and abnormal proteolytic processing of a-synuclein, particularly in the

Native unfolded a-synuclein

: POLYUBIQUITINATION

itufi;

: POLYUBIQUITINATION

itufi;

Native unfolded a-synuclein a-synuclein protofibrils (U^

Lewy Body

Lewy Body

a-synuclein protofibrils (U^

Fig. 1 A simplified hypothetical model for the pathogenesis of Parkinson's disease. (From Refs. [26] and [27].) In PARK1, mutated a-synuclein appears to aggregate more readily in transgenic models. The protofibrils appear to inhibit the proteasomal degradation of proteins (site 2). PARK4 may induce neurodegeneration by a simple gene dosage effect (site 1). Mutations in UCH-L1 may interfere with polyubiquitination of protein in the cell, or may cause aggregation of the UCH-L1 itself. The proteosomal system and its relevance for autosomal recessive forms of parkinsonism (e.g., due to parkin mutations) are outside the scope of this article.

Cell Death

Fig. 1 A simplified hypothetical model for the pathogenesis of Parkinson's disease. (From Refs. [26] and [27].) In PARK1, mutated a-synuclein appears to aggregate more readily in transgenic models. The protofibrils appear to inhibit the proteasomal degradation of proteins (site 2). PARK4 may induce neurodegeneration by a simple gene dosage effect (site 1). Mutations in UCH-L1 may interfere with polyubiquitination of protein in the cell, or may cause aggregation of the UCH-L1 itself. The proteosomal system and its relevance for autosomal recessive forms of parkinsonism (e.g., due to parkin mutations) are outside the scope of this article.

A53T mutant. In the case of the a-synuclein triplication, simple overexpression of the protein may be responsible for accumulation and neurodegeneration. Overexpression of human wild-type a-synuclein in mice produces selective decrements in DA nerve terminals in the striatum. Oxidative ligation of dopamine to a-synuclein leads to the accumulation of the a-synuclein protofibril, which may explain the relative selectivity of neurodegeneration in the dopaminergic system even though a-synuclein is widely expressed through the brain. In PARK5, the reduced catalytic activity of UCH-L1 may affect the cleavage and turnover of the protein substrate, leading to aggregation of substrate and, as a seed, of other aggregation-prone abundant proteins. Alternatively, the I93M substitution may render UCH-L1 itself prone to aggregation.[20]

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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