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Abstract
<p class="first" id="P1">The cardinal motor symptoms of Parkinson’s disease (PD) are
caused by the death of
dopaminergic neurons in the substantia nigra pars compacta (SNc). Alpha-synuclein
(aSYN) pathology and mitochondrial dysfunction have been implicated in PD pathogenesis,
but until recently it was unclear why SNc dopaminergic neurons should be particularly
vulnerable to these two types of insult. In this brief review, the evidence that SNc
dopaminergic neurons have an anatomical, physiological and biochemical phenotype that
predisposes them to mitochondrial dysfunction and synuclein pathology is summarized.
The recognition that certain traits may predispose neurons to PD-linked pathology
creates translational opportunities for slowing or stopping disease progression.
</p><p id="P2">This review summarizes evidence that selective neuronal vulnerability
in Parkinson’s
disease results from several phenotypic traits: 1) calcium-dependent, feed-forward
control of mitochondrial respiration leading to elevated reactive oxygen species and
cytosolic calcium concentration; 2) an extensive axonal arbor; and 3) a reactive neurotransmitter.
These traits increase vulnerability to genetic mutations associated with PD, age and
environmental toxins.
</p><p id="P3">
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