LRRK2 and neurodegeneration

Acta Neuropathol. 2009 Mar;117(3):227-46. doi: 10.1007/s00401-008-0478-8. Epub 2009 Jan 14.

Abstract

Mutations in leucine-rich repeat kinase 2 gene (PARK8/LRRK2) encoding the protein Lrrk2 are causative of inherited and sporadic Parkinson's disease (PD) with phenotypic manifestations of frontotemporal lobar degeneration, corticobasal degeneration and associated motor neuron disease in some patients, and with variable penetrance. Neuropathology is characterized by loss of dopaminergic neurons in the substantia nigra pars compacta in all cases with accompanying Lewy pathology, or tau pathology or without intraneuronal inclusions, thus indicating that mutations in LRRK2 are not always manifested as Lewy body disease (LBD) or as alpha-synucleinopathy. Molecular studies have not disclosed clear association between nerve cell degeneration and modifications in the kinase activity of Lrrk2, and the pathogenesis of LRRK2 mutations remains unknown. Several morphological studies have suggested that Lrrk2 is a component of Lewy bodies and aberrant neurites in sporadic PD and Dementia with Lewy bodies, whereas other studies have indicated that Lrrk2 does not participate in Lewy body composition. Likewise, some studies have shown Lrrk2 immunoreactivity in hyper-phosphorylated tau inclusions in Alzheimer's disease (AD) and other tauopathies, whereas other studies did not find Lrrk2 in hyper-phosphorylated tau inclusions. We have used three currently used anti-Lrrk2 antibodies (NB-300-268, NB-300-267 and AP7099b) and concluded that these differences are largely dependent on the antibodies used and, particularly, on the interpretation of the origin of the multiple bands of low molecular weight species, in addition to the band corresponding to full-length Lrrk2, that recognize the majority of these antibodies. A review of the available data and our results indicate that full-length Lrrk2 is not a major component of Lewy bodies in LBDs, and of hyper-phosphorylated tau inclusions in AD and tauopathies. Bands of low molecular weight are probably not the result of post-mortem artefacts as they are also present in cultured cells processed under optimal conditions. Truncated forms of Lrrk2 and additional transcripts related with LRRK2, in the absence of spliced forms of Lrrk2 may account for Lrrk2 immunoreactivity in distinct intraneuronal inclusions.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alzheimer Disease / etiology
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Animals
  • Antibody Specificity*
  • Brain / metabolism
  • Brain / pathology
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Mutation
  • Nerve Degeneration / genetics
  • Nerve Degeneration / metabolism*
  • Neurodegenerative Diseases / metabolism
  • Parkinson Disease / etiology
  • Parkinson Disease / metabolism*
  • Parkinson Disease / pathology
  • Protein Serine-Threonine Kinases / chemistry
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*

Substances

  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Protein Serine-Threonine Kinases