Lrrk2 and chronic inflammation are linked to pallido-ponto-nigral degeneration caused by the N279K tau mutation.
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.
Miklossy
Judith
J
Kinsmen Laboratory of Neurological Research, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, Canada, V6T 1Z3. judithmiklossy@bluewin.ch
Qing
Hong
H
Guo
Jian-Ping
JP
Yu
Sheng
S
Wszolek
Zbigniew K
ZK
Calne
Donald
D
McGeer
Edith G
EG
McGeer
Patrick L
PL
D000328:Adult; D000595:Amino Acid Sequence; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D002908:Chronic Disease; D003704:Dementia / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D007249:Inflammation; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
D016875:tau Proteins; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases