LRRK2 kinase in Parkinson's disease

TY - JOUR

T1 - LRRK2 kinase in Parkinson's disease

AU - Alessi, Dario R

AU - Sammler, Esther

PY - 2018/4/6

Y1 - 2018/4/6

N2 - Despite intensive research, attempts to pause or even just slow the progression of Parkinson's disease (PD) have thus far failed. Although most cases of PD are idiopathic and with largely unknown aetiology, mutations in ∼20 genes, including LRRK2 (leucine-rich repeat kinase 2), cause rare genetic Parkinsonism. All pathogenic mutations in LRRK2 result in hyperactivation of the LRRK2 kinase, offering the prospect of elaborating disease-modifying treatments. Indeed, LRRK2 inhibitors have entered phase 1 clinical trials. Data are also emerging for LRRK2 involvement in idiopathic PD, suggesting that inhibitors may benefit patients beyond those carrying LRRK2 mutations. Recent advances point toward a role for LRRK2 in regulating autophagy, an intracellular process that delivers cytoplasmic constituents to the lysosome for degradation and recycling. LRRK2 phosphorylates a subgroup of RAB proteins and regulates their ability to bind cognate effector proteins. Additionally, LRRK2 is highly expressed in immune cells. Intriguing research indicates that, in early life, increased LRRK2 activity may protect against opportunistic pathogenic infection but then later increases the risk of developing PD, a concept called antagonistic pleiotropy.

AB - Despite intensive research, attempts to pause or even just slow the progression of Parkinson's disease (PD) have thus far failed. Although most cases of PD are idiopathic and with largely unknown aetiology, mutations in ∼20 genes, including LRRK2 (leucine-rich repeat kinase 2), cause rare genetic Parkinsonism. All pathogenic mutations in LRRK2 result in hyperactivation of the LRRK2 kinase, offering the prospect of elaborating disease-modifying treatments. Indeed, LRRK2 inhibitors have entered phase 1 clinical trials. Data are also emerging for LRRK2 involvement in idiopathic PD, suggesting that inhibitors may benefit patients beyond those carrying LRRK2 mutations. Recent advances point toward a role for LRRK2 in regulating autophagy, an intracellular process that delivers cytoplasmic constituents to the lysosome for degradation and recycling. LRRK2 phosphorylates a subgroup of RAB proteins and regulates their ability to bind cognate effector proteins. Additionally, LRRK2 is highly expressed in immune cells. Intriguing research indicates that, in early life, increased LRRK2 activity may protect against opportunistic pathogenic infection but then later increases the risk of developing PD, a concept called antagonistic pleiotropy.

KW - Animals

KW - Communicable Diseases

KW - Genes, Dominant

KW - Humans

KW - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2

KW - Mice

KW - Mutation, Missense

KW - Parkinson Disease

KW - Phosphorylation

KW - Signal Transduction

KW - rab GTP-Binding Proteins

KW - Journal Article

UR - https://www.scopus.com/pages/publications/85045016558

U2 - 10.1126/science.aar5683

DO - 10.1126/science.aar5683

M3 - Comment/debate

C2 - 29622645

SN - 0036-8075

VL - 360

SP - 36

EP - 37

JO - Science

JF - Science

IS - 6384

ER -