Involvement of the peripheral nervous system in synucleinopathies, tauopathies and other neurodegenerative proteinopathies of the brain

Wakabayashi, Keiji; Mori, Fumiaki; Tanji, Kunikazu; Orimo, Satoshi; Takahashi, Hitoshi

doi:10.1007/s00401-010-0706-x

Cited by 134 publications

(125 citation statements)

References 172 publications

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“…It is not restricted to specific dopaminergic brainstem nuclei, but involves multiple areas of the central, autonomic, and peripheral nervous system, the retina, sympathetic and parasympathetic ganglia and nerves, skin, salivary glands, and other organs (for rev. see [23,24]). The pathology of NM symptoms in PD has been reviewed recently [20,[25][26][27][28].…”

Section: Introductionmentioning

confidence: 94%

Synuclein deposition and non-motor symptoms in Parkinson disease

Jellinger¹

2011

Journal of the Neurological Sciences

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Section: Introductionmentioning

confidence: 94%

Synuclein deposition and non-motor symptoms in Parkinson disease

Jellinger¹

2011

Journal of the Neurological Sciences

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“…The rational for this prodrome is based on the staging system of Braak, which suggested that the pathological process may not start in the SNpc (Braak et al). Examination of SNCA deposition patterns shows that the deposition of SNCA is not restricted to the brain, with deposits found in the olfactory bulb, peripheral nervous system, enteric nervous system (ENS), cardiac, and pelvic plexuses, etc (Wakabayashi et al, 2010 (Parkkinen et al, 2008). The speed of progression through the early stages remains unclear.…”

Section: Aims Of This Phd Projectmentioning

confidence: 99%

Glucocerebrosidase mutations and the pathogenesis of Parkinson disease

Beavan

Schapira

2013

Annals of Medicine

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“…αS pathology has also been found in the peripheral nervous system (PNS): for example, in the enteric and pelvic plexus (19,20). And it has been suggested that αS pathology might originate in the nerves of the PNS and spread to the CNS (14).…”

mentioning

confidence: 99%

Intramuscular injection of α-synuclein induces CNS α-synuclein pathology and a rapid-onset motor phenotype in transgenic mice

Sacino¹,

Brooks²,

Thomas³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

289

343

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It has been hypothesized that α-synuclein (αS) misfolding may begin in peripheral nerves and spread to the central nervous system (CNS), leading to Parkinson disease and related disorders. Although recent data suggest that αS pathology can spread within the mouse brain, there is no direct evidence for spread of disease from a peripheral site. In the present study, we show that hind limb intramuscular (IM) injection of αS can induce pathology in the CNS in the human Ala53Thr (M83) and wild-type (M20) αS transgenic (Tg) mouse models. Within 2-3 mo after IM injection in αS homozygous M83 Tg mice and 3-4 mo for hemizygous M83 Tg mice, these animals developed a rapid, synchronized, and predictable induction of widespread CNS αS inclusion pathology, accompanied by astrogliosis, microgliosis, and debilitating motor impairments. In M20 Tg mice, starting at 4 mo after IM injection, we observed αS inclusion pathology in the spinal cord, but motor function remained intact. Transection of the sciatic nerve in the M83 Tg mice significantly delayed the appearance of CNS pathology and motor symptoms, demonstrating the involvement of retrograde transport in inducing αS CNS inclusion pathology. Outside of scrapie-mediated prion disease, to our knowledge, this findiing is the first evidence that an entire neurodegenerative proteinopathy associated with a robust, lethal motor phenotype can be initiated by peripheral inoculation with a pathogenic protein. Furthermore, this facile, synchronized rapid-onset model of α-synucleinopathy will be highly valuable in testing disease-modifying therapies and dissecting the mechanism(s) that drive αS-induced neurodegeneration.amyloid | Parkinson disease S ynucleinopathies are a group of diseases defined by the presence of amyloidogenic α-synuclein (αS) inclusions that can occur in neurons and glia of the central nervous system (CNS) (1-4). In Parkinson disease (PD), a causative role for αS has been established via the discovery of mutations in the αS gene SNCA resulting in autosomal-dominant PD (4-11). Although αS inclusions (e.g., Lewy bodies) are the hallmark pathology of PD, how they contribute to disease pathogenesis remains controversial (1,3,4,12).Postmortem studies have suggested that αS pathology may spread following neuroanatomical tracts (13-15) and between cells (16-18). αS pathology has also been found in the peripheral nervous system (PNS): for example, in the enteric and pelvic plexus (19,20). And it has been suggested that αS pathology might originate in the nerves of the PNS and spread to the CNS (14). Experimentally, it has been reported that intracerebral injections of preformed amyloidogenic αS fibrils in nontransgenic (nTg) and αS transgenic (Tg) mice induce the formation of intracellular αS inclusions that appear to progress from the site of injection (21-26). Collectively, these studies support the notion that αS inclusion pathology may propagate via a prion-like conformational self-templating mechanism (27, 28). A caveat of the direct intracerebral injection of αS is tha...

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Involvement of the peripheral nervous system in synucleinopathies, tauopathies and other neurodegenerative proteinopathies of the brain

Cited by 134 publications

References 172 publications

Synuclein deposition and non-motor symptoms in Parkinson disease

Synuclein deposition and non-motor symptoms in Parkinson disease

Glucocerebrosidase mutations and the pathogenesis of Parkinson disease

Intramuscular injection of α-synuclein induces CNS α-synuclein pathology and a rapid-onset motor phenotype in transgenic mice

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