Association between cardiac denervation and parkinsonism caused by α‐synuclein gene triplication

Abstract

Parkinson's disease patients frequently have symptoms and signs of autonomic nervous dysfunction that are the source of considerable disability. Recent studies have revealed that most patients with Parkinson's disease, and all with Parkinson's disease-associated orthostatic hypotension, have a loss of cardiac sympathetic innervation. Familial Parkinson's disease, caused by mutation of the gene encoding alpha-synuclein, also features orthostatic hypotension, sympathetic neurocirculatory failure and cardiac sympathetic denervation. We have recently described a whole-gene triplication of alpha-synuclein causing Lewy body parkinsonism in a large, well characterized family called the 'Iowa kindred'. Here we report the results of cardiac PET scanning using the sympathoneural imaging agent, 6-[18F]fluorodopamine in affected and unaffected members of this kindred. Four family members were studied, two with parkinsonism, one clinically normal and one with benign essential tremor alone. Both affected members had obvious loss of cardiac sympathetic innervation; the unaffected member had normal innervation, as did the member with isolated essential tremor. The results indicate that, in this family, where disease is caused by overexpression of normal alpha-synuclein, cardiac sympathetic denervation cosegregates with parkinsonism. Post-mortem studies have demonstrated synuclein-positive Lewy body formation in the brains of individuals with parkinsonism who were also in the family described here and who also carry this triplication. These results indicate that both parkinsonism and cardiac sympathetic denervation can result from an excess of normal synuclein.

Amyloidogenesis of Natively Unfolded Proteins

“…Therefore, high protein concentration is predicted to accelerate fibrillation, as is in fact observed in vitro [108,114] and in the PD patient with the α-synuclein gene triplication [83][84][85]. The data suggest that the key partially folded conformation, once formed, oligomerizes rapidly to form fibrils.…”

“…For example, a direct role for α-synuclein in the neurodegenerative processes in PD is demonstrated by genetic evidence and autosomal dominant early-onset PD is associated with three different missense mutations in the α-synuclein gene, corresponding to A30P, E46K, and A53T substitutions in α-synuclein [80][81][82] or with the hyper-expression of the wild type α-synuclein protein due to gene triplication [83][84][85]. Antibodies to α-synuclein detect this protein in LBs and LNs, the hallmark lesions of PD, a substantial portion of fibrillar material in these specific inclusions was shown to be comprise of α-synuclein, and insoluble α-synuclein filaments were recovered from purified LBs [86,87].…”

The Anti-Parkinsonian Drug Selegiline Delays the Nucleation Phase of α-Synuclein Aggregation Leading to the Formation of Nontoxic Species

“…These and other neurodegenerative disorders characterized by α-syn inclusions are collectively known as synucleinopathies. 5 Furthermore, a central role of α-syn in the pathogenesis of PD is supported by strong genetic evidence: [6][7][8][9][10] (1) three missense mutations in α-syn (A30P, A53T, and E46K) are associated with autosomal-dominant inherited forms of PD; (2) duplication and triplication in a region that encompasses the α-syn gene on chromosome 4 are sufficient to cause familial PD; and (3) all familial PD mutations accelerated the aggregation of α-syn in vitro, but not necessarily fibrillation. 7,[11][12][13] Selegiline (Sel; R(−)-deprenyl) (Fig.…”

Dynamic Aspects of Amyloid Fibrils of α-Synuclein Related to the Pathogenesis of Parkinson’s Disease

“…The major component in these inclusions is α-synuclein (αSyn), which is a 140 amino acid protein of unknown function, usually abundant in presynaptic terminals of nerve cells [2]. Missense mutations [3][4][5] and overexpression due to gene duplication or triplication [6][7][8] of this protein are known to cause autosomal dominant early-onset PD. αSyn is thus involved with the pathogenesis of PD.…”