Biochemical and pathological characterization of Lrrk2.

Abstract

OBJECTIVE:

Mutations in leucine-rich repeat kinase 2 (LRRK2) recently have been identified as the most common genetic cause of late-onset sporadic and familial Parkinson's disease (PD). The studies herein explore the biological and pathological properties of Lrrk2.

METHODS:

Genetic analysis was performed to identify autopsied patients with the most common Lrrk2 mutation (G2019S). Using an antibody specific to Lrrk2, the biochemical and immunocytochemical distribution of Lrrk2 was assessed.

RESULTS:

Three patients with the G2019S Lrrk2 mutation were identified. Two patients demonstrated classic PD with Lewy bodies, although concurrent pathological changes consistent with Alzheimer's disease were also present in one of these individuals. The third patient was characterized by parkinsonism without Lewy bodies but demonstrated dystrophic neurites in the substantia nigra intensely stained for Lrrk2. Lrrk2 accumulations were unique to this patient and Lrrk2 was not detected in other types of pathological inclusions. Biochemical analysis showed that Lrrk2 is predominantly a soluble approximately 250 kDa cytoplasmic protein expressed throughout the brain but also in many other organs.

INTERPRETATION:

The reasons for the selective predisposition of patients with mutations in LRRK2 to develop parkinsonism remains unclear, but Lrrk2 mutations may prime select neuronal populations to cellular insults that can lead to aberrant protein aggregation.

• Authors: Benoit I Giasson, Jason P Covy, Nancy M Bonini, Howard I Hurtig, Matthew J Farrer, John Q Trojanowski, Vivianna M Van Deerlin
• Journal: Annals of neurology (Ann Neurol) Vol. 59 Issue 2 Pg. 315-22 (Feb 2006) ISSN: 0364-5134 [Print] United States
• PMID: 16437584 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Adult
• Aged
• Aged, 80 and over
• Amino Acid Sequence
• Animals
• Blotting, Western (methods)
• Brain (metabolism, pathology)
• Cell Line
• DNA Mutational Analysis (methods)
• Female
• Genetic Predisposition to Disease
• Glycine (genetics)
• Humans
• Immunohistochemistry (methods)
• Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
• Male
• Mice
• Middle Aged
• Molecular Weight
• Mutation
• Parkinson Disease (genetics, metabolism, pathology)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Serine (genetics)
• Time Factors
• Transfection (methods)
• alpha-Synuclein (metabolism)