Familial knockin mutation of LRRK2 causes lysosomal dysfunction and accumulation of endogenous insoluble α-synuclein in neurons

Jason Schapansky, Saurabh Khasnavis, Mark P. DeAndrade, Jonathan D. Nardozzi, Samuel R. Falkson, Justin D. Boyd, John B. Sanderson, Tim Bartels, Heather L Melrose, Matthew J. LaVoie

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Missense mutations in the multi-domain kinase LRRK2 cause late onset familial Parkinson's disease. They most commonly with classic proteinopathy in the form of Lewy bodies and Lewy neurites comprised of insoluble α-synuclein, but in rare cases can also manifest tauopathy. The normal function of LRRK2 has remained elusive, as have the cellular consequences of its mutation. Data from LRRK2 null model organisms and LRRK2-inhibitor treated animals support a physiological role for LRRK2 in regulating lysosome function. Since idiopathic and LRRK2-linked PD are associated with the intraneuronal accumulation of protein aggregates, a series of critical questions emerge. First, how do pathogenic mutations that increase LRRK2 kinase activity affect lysosome biology in neurons? Second, are mutation-induced changes in lysosome function sufficient to alter the metabolism of α-synuclein? Lastly, are changes caused by pathogenic mutation sensitive to reversal with LRRK2 kinase inhibitors? Here, we report that mutation of LRRK2 induces modest but significant changes in lysosomal morphology and acidification, and decreased basal autophagic flux when compared to WT neurons. These changes were associated with an accumulation of detergent-insoluble α-synuclein and increased neuronal release of α-synuclein and were reversed by pharmacologic inhibition of LRRK2 kinase activity. These data demonstrate a critical and disease-relevant influence of native neuronal LRRK2 kinase activity on lysosome function and α-synuclein homeostasis. Furthermore, they also suggest that lysosome dysfunction, altered neuronal α-synuclein metabolism, and the insidious accumulation of aggregated protein over decades may contribute to pathogenesis in this late-onset form of familial PD.

Original languageEnglish (US)
Pages (from-to)26-35
Number of pages10
JournalNeurobiology of Disease
Volume111
DOIs
StatePublished - Mar 1 2018

Fingerprint

Synucleins
Lysosomes
Phosphotransferases
Neurons
Mutation
Tauopathies
Lewy Bodies
Neurites
Missense Mutation
Detergents
Parkinson Disease
Homeostasis

Keywords

  • LRRK2
  • Lysosome
  • Parkinson's disease
  • Tau
  • Tau phosphorylation
  • α-Synuclein

ASJC Scopus subject areas

  • Neurology

Cite this

Schapansky, J., Khasnavis, S., DeAndrade, M. P., Nardozzi, J. D., Falkson, S. R., Boyd, J. D., ... LaVoie, M. J. (2018). Familial knockin mutation of LRRK2 causes lysosomal dysfunction and accumulation of endogenous insoluble α-synuclein in neurons. Neurobiology of Disease, 111, 26-35. https://doi.org/10.1016/j.nbd.2017.12.005

Familial knockin mutation of LRRK2 causes lysosomal dysfunction and accumulation of endogenous insoluble α-synuclein in neurons. / Schapansky, Jason; Khasnavis, Saurabh; DeAndrade, Mark P.; Nardozzi, Jonathan D.; Falkson, Samuel R.; Boyd, Justin D.; Sanderson, John B.; Bartels, Tim; Melrose, Heather L; LaVoie, Matthew J.

In: Neurobiology of Disease, Vol. 111, 01.03.2018, p. 26-35.

Research output: Contribution to journalArticle

Schapansky, J, Khasnavis, S, DeAndrade, MP, Nardozzi, JD, Falkson, SR, Boyd, JD, Sanderson, JB, Bartels, T, Melrose, HL & LaVoie, MJ 2018, 'Familial knockin mutation of LRRK2 causes lysosomal dysfunction and accumulation of endogenous insoluble α-synuclein in neurons', Neurobiology of Disease, vol. 111, pp. 26-35. https://doi.org/10.1016/j.nbd.2017.12.005
Schapansky, Jason ; Khasnavis, Saurabh ; DeAndrade, Mark P. ; Nardozzi, Jonathan D. ; Falkson, Samuel R. ; Boyd, Justin D. ; Sanderson, John B. ; Bartels, Tim ; Melrose, Heather L ; LaVoie, Matthew J. / Familial knockin mutation of LRRK2 causes lysosomal dysfunction and accumulation of endogenous insoluble α-synuclein in neurons. In: Neurobiology of Disease. 2018 ; Vol. 111. pp. 26-35.
@article{8399b9665084468082f547ed13213bea,
title = "Familial knockin mutation of LRRK2 causes lysosomal dysfunction and accumulation of endogenous insoluble α-synuclein in neurons",
abstract = "Missense mutations in the multi-domain kinase LRRK2 cause late onset familial Parkinson's disease. They most commonly with classic proteinopathy in the form of Lewy bodies and Lewy neurites comprised of insoluble α-synuclein, but in rare cases can also manifest tauopathy. The normal function of LRRK2 has remained elusive, as have the cellular consequences of its mutation. Data from LRRK2 null model organisms and LRRK2-inhibitor treated animals support a physiological role for LRRK2 in regulating lysosome function. Since idiopathic and LRRK2-linked PD are associated with the intraneuronal accumulation of protein aggregates, a series of critical questions emerge. First, how do pathogenic mutations that increase LRRK2 kinase activity affect lysosome biology in neurons? Second, are mutation-induced changes in lysosome function sufficient to alter the metabolism of α-synuclein? Lastly, are changes caused by pathogenic mutation sensitive to reversal with LRRK2 kinase inhibitors? Here, we report that mutation of LRRK2 induces modest but significant changes in lysosomal morphology and acidification, and decreased basal autophagic flux when compared to WT neurons. These changes were associated with an accumulation of detergent-insoluble α-synuclein and increased neuronal release of α-synuclein and were reversed by pharmacologic inhibition of LRRK2 kinase activity. These data demonstrate a critical and disease-relevant influence of native neuronal LRRK2 kinase activity on lysosome function and α-synuclein homeostasis. Furthermore, they also suggest that lysosome dysfunction, altered neuronal α-synuclein metabolism, and the insidious accumulation of aggregated protein over decades may contribute to pathogenesis in this late-onset form of familial PD.",
keywords = "LRRK2, Lysosome, Parkinson's disease, Tau, Tau phosphorylation, α-Synuclein",
author = "Jason Schapansky and Saurabh Khasnavis and DeAndrade, {Mark P.} and Nardozzi, {Jonathan D.} and Falkson, {Samuel R.} and Boyd, {Justin D.} and Sanderson, {John B.} and Tim Bartels and Melrose, {Heather L} and LaVoie, {Matthew J.}",
year = "2018",
month = "3",
day = "1",
doi = "10.1016/j.nbd.2017.12.005",
language = "English (US)",
volume = "111",
pages = "26--35",
journal = "Neurobiology of Disease",
issn = "0969-9961",
publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - Familial knockin mutation of LRRK2 causes lysosomal dysfunction and accumulation of endogenous insoluble α-synuclein in neurons

AU - Schapansky, Jason

AU - Khasnavis, Saurabh

AU - DeAndrade, Mark P.

AU - Nardozzi, Jonathan D.

AU - Falkson, Samuel R.

AU - Boyd, Justin D.

AU - Sanderson, John B.

AU - Bartels, Tim

AU - Melrose, Heather L

AU - LaVoie, Matthew J.

PY - 2018/3/1

Y1 - 2018/3/1

N2 - Missense mutations in the multi-domain kinase LRRK2 cause late onset familial Parkinson's disease. They most commonly with classic proteinopathy in the form of Lewy bodies and Lewy neurites comprised of insoluble α-synuclein, but in rare cases can also manifest tauopathy. The normal function of LRRK2 has remained elusive, as have the cellular consequences of its mutation. Data from LRRK2 null model organisms and LRRK2-inhibitor treated animals support a physiological role for LRRK2 in regulating lysosome function. Since idiopathic and LRRK2-linked PD are associated with the intraneuronal accumulation of protein aggregates, a series of critical questions emerge. First, how do pathogenic mutations that increase LRRK2 kinase activity affect lysosome biology in neurons? Second, are mutation-induced changes in lysosome function sufficient to alter the metabolism of α-synuclein? Lastly, are changes caused by pathogenic mutation sensitive to reversal with LRRK2 kinase inhibitors? Here, we report that mutation of LRRK2 induces modest but significant changes in lysosomal morphology and acidification, and decreased basal autophagic flux when compared to WT neurons. These changes were associated with an accumulation of detergent-insoluble α-synuclein and increased neuronal release of α-synuclein and were reversed by pharmacologic inhibition of LRRK2 kinase activity. These data demonstrate a critical and disease-relevant influence of native neuronal LRRK2 kinase activity on lysosome function and α-synuclein homeostasis. Furthermore, they also suggest that lysosome dysfunction, altered neuronal α-synuclein metabolism, and the insidious accumulation of aggregated protein over decades may contribute to pathogenesis in this late-onset form of familial PD.

AB - Missense mutations in the multi-domain kinase LRRK2 cause late onset familial Parkinson's disease. They most commonly with classic proteinopathy in the form of Lewy bodies and Lewy neurites comprised of insoluble α-synuclein, but in rare cases can also manifest tauopathy. The normal function of LRRK2 has remained elusive, as have the cellular consequences of its mutation. Data from LRRK2 null model organisms and LRRK2-inhibitor treated animals support a physiological role for LRRK2 in regulating lysosome function. Since idiopathic and LRRK2-linked PD are associated with the intraneuronal accumulation of protein aggregates, a series of critical questions emerge. First, how do pathogenic mutations that increase LRRK2 kinase activity affect lysosome biology in neurons? Second, are mutation-induced changes in lysosome function sufficient to alter the metabolism of α-synuclein? Lastly, are changes caused by pathogenic mutation sensitive to reversal with LRRK2 kinase inhibitors? Here, we report that mutation of LRRK2 induces modest but significant changes in lysosomal morphology and acidification, and decreased basal autophagic flux when compared to WT neurons. These changes were associated with an accumulation of detergent-insoluble α-synuclein and increased neuronal release of α-synuclein and were reversed by pharmacologic inhibition of LRRK2 kinase activity. These data demonstrate a critical and disease-relevant influence of native neuronal LRRK2 kinase activity on lysosome function and α-synuclein homeostasis. Furthermore, they also suggest that lysosome dysfunction, altered neuronal α-synuclein metabolism, and the insidious accumulation of aggregated protein over decades may contribute to pathogenesis in this late-onset form of familial PD.

KW - LRRK2

KW - Lysosome

KW - Parkinson's disease

KW - Tau

KW - Tau phosphorylation

KW - α-Synuclein

UR - http://www.scopus.com/inward/record.url?scp=85038101157&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85038101157&partnerID=8YFLogxK

U2 - 10.1016/j.nbd.2017.12.005

DO - 10.1016/j.nbd.2017.12.005

M3 - Article

C2 - 29246723

AN - SCOPUS:85038101157

VL - 111

SP - 26

EP - 35

JO - Neurobiology of Disease

JF - Neurobiology of Disease

SN - 0969-9961

ER -