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Parkinson's disease concept is classically restricted to a rigid-akinetic syndrome due to a nigro-striatal dopaminergic depletion. This concept ignored the widespread extension of neuropathologic findings across the CNS. Moreover detailed clinical studies showed that patients suffer a constellation of other symptoms and signs such as anosmia, constipation, cardiovascular disautonomia, neuropsychologic and neuropsychiatric disorders, dementia and sleep changes. Taken together these evidences have lead to the idea that Parkinson's disease is a multisystemic disease of the nervous system. Braak et al. have proposed first, a staging system for the neuropathologic burden into the CNS and second, a "dual-hit" pathogenic hypothesis implicating a putative exogenous agent acquired through nasal route passing into the digestive tube and reaching the medulla following the vagus nerve. This hypothesis has received many criticisms. Our own findings in a family carrying a single aminoacid change (E46K) in alpha-synuclein segregating with a severe autosomal dominant Parkinson's disease phenotype, suggest that cardiac sympathetic denervation is the first step in this disease.