Lrrk2 and chronic inflammation are linked to pallido-ponto-nigral degeneration caused by the N279K tau mutation
Identifieur interne : 001663 ( Main/Exploration ); précédent : 001662; suivant : 001664Lrrk2 and chronic inflammation are linked to pallido-ponto-nigral degeneration caused by the N279K tau mutation
Auteurs : Judith Miklossy [Canada, Suisse] ; Hong Qing [Canada] ; Jian-Ping Guo [Canada] ; Sheng Yu [Canada] ; Zbigniew K. Wszolek [États-Unis] ; Donald Calne [Canada] ; Edith G. Mcgeer [Canada] ; Patrick L. Mcgeer [Canada]Source :
- Acta Neuropathologica [ 0001-6322 ] ; 2007-09-01.
English descriptors
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Abstract
Abstract: Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) have been identified in families with autosomal dominant late-onset Parkinson disease (PD). Lrrk2 is a phylogenetically conserved, ubiquitous protein, which is constitutively expressed in various cells including neurons and glial cells of human brain. We recently reported that Lrrk2 is identified in Lewy bodies in PD as well as in neuronal and glial inclusions in several other neurodegenerative disorders. Here we show that Lrrk2 is closely associated with the tau-positive inclusions in eight members of a family with frontotemporal dementia of the pallido-ponto-nigral degeneration type linked to the chromosome 17 N279K tau mutation (N279K/FTDP-17/PPND). Lrrk2 is colocalized with tau in oligodendroglial coiled bodies and intracytoplasmic neuronal inclusions. HLA-DR positive reactive microglia and ICAM-1 positive reactive astrocytes accumulated in affected areas demonstrating that inflammatory processes are also involved in the disease pathogenesis. Western blot analysis of soluble extracts of N279K/FTDP-17/PPND brain tissue suggests that C-terminal fragment(s) of apparent 64–75 kDa molecular weight may be the major Lrrk2 species in pathological deposits. The possibility that Lrrk2 is linked with various neurodegenerative disorders through the ubiquitin proteosome pathway is discussed. The results indicate that Lrrk2 is linked to frontotemporal atrophy of PPND type caused by N279K tau mutation. They also show that chronic inflammation is involved in the pathogenesis of N279K/FTDP-17/PPND.
Url:
DOI: 10.1007/s00401-007-0230-9
Affiliations:
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Lrrk2 is a phylogenetically conserved, ubiquitous protein, which is constitutively expressed in various cells including neurons and glial cells of human brain. We recently reported that Lrrk2 is identified in Lewy bodies in PD as well as in neuronal and glial inclusions in several other neurodegenerative disorders. Here we show that Lrrk2 is closely associated with the tau-positive inclusions in eight members of a family with frontotemporal dementia of the pallido-ponto-nigral degeneration type linked to the chromosome 17 N279K tau mutation (N279K/FTDP-17/PPND). Lrrk2 is colocalized with tau in oligodendroglial coiled bodies and intracytoplasmic neuronal inclusions. HLA-DR positive reactive microglia and ICAM-1 positive reactive astrocytes accumulated in affected areas demonstrating that inflammatory processes are also involved in the disease pathogenesis. Western blot analysis of soluble extracts of N279K/FTDP-17/PPND brain tissue suggests that C-terminal fragment(s) of apparent 64–75 kDa molecular weight may be the major Lrrk2 species in pathological deposits. The possibility that Lrrk2 is linked with various neurodegenerative disorders through the ubiquitin proteosome pathway is discussed. The results indicate that Lrrk2 is linked to frontotemporal atrophy of PPND type caused by N279K tau mutation. They also show that chronic inflammation is involved in the pathogenesis of N279K/FTDP-17/PPND.</div></front></TEI><affiliations><list><country><li>Canada</li><li>Suisse</li><li>États-Unis</li></country><region><li>Floride</li></region></list><tree><country name="Canada"><noRegion><name sortKey="Miklossy, Judith" sort="Miklossy, Judith" uniqKey="Miklossy J" first="Judith" last="Miklossy">Judith Miklossy</name></noRegion><name sortKey="Calne, Donald" sort="Calne, Donald" uniqKey="Calne D" first="Donald" last="Calne">Donald Calne</name><name sortKey="Calne, Donald" sort="Calne, Donald" uniqKey="Calne D" first="Donald" last="Calne">Donald Calne</name><name sortKey="Guo, Jian Ping" sort="Guo, Jian Ping" uniqKey="Guo J" first="Jian-Ping" last="Guo">Jian-Ping Guo</name><name sortKey="Mcgeer, Edith G" sort="Mcgeer, Edith G" uniqKey="Mcgeer E" first="Edith G." last="Mcgeer">Edith G. Mcgeer</name><name sortKey="Mcgeer, Patrick L" sort="Mcgeer, Patrick L" uniqKey="Mcgeer P" first="Patrick L." last="Mcgeer">Patrick L. Mcgeer</name><name sortKey="Qing, Hong" sort="Qing, Hong" uniqKey="Qing H" first="Hong" last="Qing">Hong Qing</name><name sortKey="Yu, Sheng" sort="Yu, Sheng" uniqKey="Yu S" first="Sheng" last="Yu">Sheng Yu</name></country><country name="Suisse"><noRegion><name sortKey="Miklossy, Judith" sort="Miklossy, Judith" uniqKey="Miklossy J" first="Judith" last="Miklossy">Judith Miklossy</name></noRegion></country><country name="États-Unis"><region name="Floride"><name sortKey="Wszolek, Zbigniew K" sort="Wszolek, Zbigniew K" uniqKey="Wszolek Z" first="Zbigniew K." last="Wszolek">Zbigniew K. Wszolek</name></region><name sortKey="Wszolek, Zbigniew K" sort="Wszolek, Zbigniew K" uniqKey="Wszolek Z" first="Zbigniew K." last="Wszolek">Zbigniew K. Wszolek</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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