The etiopathogenesis of Parkinson disease and suggestions for future research. Part II.
Irene Litvan,Marie-Françoise Chesselet,Thomas Gasser,Donato A. Di Monte,Davis Parker,Theo Hagg,John Hardy,Peter Jenner,Richard H. Myers,Donald D. Price,Mark Hallett,William J. Langston,Anthony E. Lang,Glenda M. Halliday,Walter A. Rocca,Charles Duyckaerts,Dennis W. Dickson,Yoav Ben-Shlomo,Christopher G. Goetz,Eldad Melamed +19 more
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TLDR
The second part of this two-part, state-of-the-art review by leaders in PD research critically examines the research field to identify areas for which new knowledge and ideas might be helpful for treatment purposes.Abstract:
We are at a critical juncture in our knowledge of the etiology and pathogenesis of Parkinson disease (PD). It is clear that PD is not a single entity simply resulting from a dopaminergic deficit; rather it is most likely caused by a combination of genetic and environmental factors and, although there is extensive new information on the etiology and pathogenesis of PD that may advance its treatment, new syntheses of this information are needed. The first part of this two-part, state-of-the-art review by leaders in Parkinson research critically examines the field to identify where new knowledge and ideas might be helpful for treatment purposes. Topics reviewed in Part I include the definition of the disease, neuropathologic contributions, and epidemiologic, environmental, and demographic issues.
### Current Knowledge
The definition of idiopathic Parkinson disease (PD) remains controversial. Classically, it includes a characteristic motor phenotype (1) and a distinctive neuropathology and substantial loss of dopaminergic neurons from the substantia nigra associated with the presence of α-synuclein-positive inclusions in the cell body (Lewy bodies) and processes (Lewy neurites) of specific neurons of the brainstem.
### Parkinson Syndrome Without Synucleinopathy
Some genetically determined Parkinson syndromes resemble, sometimes closely, idiopathic PD, but differ from it neuropathologically, sometimes substantially. In particular, a number of juvenile-onset autosomal recessive cases of familial Parkinson syndrome do not have α-synuclein lesions (2), contrasting with the autosomal dominant forms of the disease which often have unusual types of lesions (3-5). The recently identified leucine-rich repeat kinase 2 ( LRRK2, Park-8 ) mutations produce variable pathologic phenotypes. Although the most common is Lewy body disease, nigral degeneration with ubiquitin inclusions or, in a few cases, even pathologic changes more typical of frontotemporal lobar degeneration or progressive supranuclear palsy have been described in patients with LRRK2 mutations (6). Two recent reports insist on the high prevalence of Lewy bodies in the LRRK2 mutations (7 …read more
Citations
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Missing pieces in the Parkinson's disease puzzle.
Jose A. Obeso,Maria C. Rodriguez-Oroz,Christopher G. Goetz,Concepcion Marin,Concepcion Marin,Jeffrey H. Kordower,Manuel Rodriguez,Manuel Rodriguez,Etienne C. Hirsch,Matthew J. Farrer,Anthony H.V. Schapira,Glenda M. Halliday +11 more
TL;DR: A series of critical issues that researchers need to address to stand a better chance of solving the different challenges posed by Parkinson's disease are discussed.
Journal ArticleDOI
Does neuroinflammation fan the flame in neurodegenerative diseases
TL;DR: The hallmarks of acute and chronic inflammatory responses in the CNS are reviewed, the reasons why microglial activation represents a convergence point for diverse stimuli that may promote or compromise neuronal survival, and the epidemiologic, pharmacologic and genetic evidence implicating neuroinflammation in the pathophysiology of several neurodegenerative diseases are reviewed.
Journal ArticleDOI
Invited Article: Nervous system pathology in sporadic Parkinson disease
Heiko Braak,Kelly Del Tredici +1 more
TL;DR: The Lewy body pathology associated with the synucleinopathy sporadic (or idiopathic) PD, the most widespread form of parkinsonism, is referred to.
Journal ArticleDOI
Neuropathology, biochemistry, and biophysics of α-synuclein aggregation
TL;DR: This paper provides an overview of the biochemistry, biophysics, and neuropathology of α‐synuclein aggregation and possesses remarkable conformational plasticity.
Journal ArticleDOI
Neuropathology of sporadic Parkinson's disease: Evaluation and changes of concepts
TL;DR: Recent research has improved both the clinical and neuropathological diagnostic criteria of PD and provided insights into the development and staging of αSyn and Lewy pathologies and has been useful in understanding the pathogenesis of PD.
References
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Journal ArticleDOI
Staging of brain pathology related to sporadic Parkinson’s disease
TL;DR: This study traces the course of the pathology in incidental and symptomatic Parkinson cases proposing a staging procedure based upon the readily recognizable topographical extent of the lesions.
Journal ArticleDOI
Mutation in the α-synuclein gene identified in families with Parkinson's disease
Mihael H. Polymeropoulos,Christian Lavedan,Elisabeth Leroy,Susan E. Ide,Anindya Dehejia,Amalia Dutra,Brian L. Pike,Holly Root,Jeffrey Rubenstein,Rebecca Boyer,Edward S. Stenroos,Settara C. Chandrasekharappa,Aglaia Athanassiadou,Theodore Papapetropoulos,William G. Johnson,Alice Lazzarini,Roger C. Duvoisin,Giuseppe Di Iorio,Lawrence I. Golbe,Robert L. Nussbaum +19 more
TL;DR: A mutation was identified in the α-synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, in the Italian kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype.
Journal ArticleDOI
Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism
Tohru Kitada,Shuichi Asakawa,Nobutaka Hattori,Hiroto Matsumine,Yasuhiro Yamamura,Shinsei Minoshima,Masayuki Yokochi,Yoshikuni Mizuno,Nobuyoshi Shimizu +8 more
TL;DR: Mutations in the newly identified gene appear to be responsible for the pathogenesis of Autosomal recessive juvenile parkinsonism, and the protein product is named ‘Parkin’.
Journal ArticleDOI
Parkinson's disease: Mechanisms and models
TL;DR: PD models based on the manipulation of PD genes should prove valuable in elucidating important aspects of the disease, such as selective vulnerability of substantia nigra dopaminergic neurons to the degenerative process.
Journal ArticleDOI
Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis
TL;DR: It is proposed that this chemical selectively damages cells in the substantia nigra in patients who developed marked parkinsonism after using an illicit drug intravenously.
Related Papers (5)
Mutation in the α-synuclein gene identified in families with Parkinson's disease
Mihael H. Polymeropoulos,Christian Lavedan,Elisabeth Leroy,Susan E. Ide,Anindya Dehejia,Amalia Dutra,Brian L. Pike,Holly Root,Jeffrey Rubenstein,Rebecca Boyer,Edward S. Stenroos,Settara C. Chandrasekharappa,Aglaia Athanassiadou,Theodore Papapetropoulos,William G. Johnson,Alice Lazzarini,Roger C. Duvoisin,Giuseppe Di Iorio,Lawrence I. Golbe,Robert L. Nussbaum +19 more