Mechanisms of Mutant LRRK2 Neurodegeneration

  • Mark R. CooksonEmail author
Part of the Advances in Neurobiology book series (NEUROBIOL, volume 14)


LRRK2 mutations are associated with the loss of neurons, that is to say toxicity, in patients and in experimental model systems. However, the mechanisms by which mutations can be linked to neurodegeneration are not fully defined. Here I will argue that mechanism in this context encompasses a variety of levels of information. Mutations or alterations in gene expression at a genetic level are one set of mechanisms that are reflected at the biochemical level likely in enhanced or persistent function of LRRK2. By impacting cellular pathways, prominently including changes in autophagy but also microtubule function, mitochondria and protein synthesis, in neurons and immune cells, the LRRK2 brain is primed for neurodegeneration in an age-dependent manner. These concepts have implications for not only modeling LRRK2 disease but also perhaps for Parkinson’s disease more generally, including the development of therapeutic modalities.


α-Synuclein Gene expression GTPase Kinase Mutations Pleomorphic risk locus Rab7L1 



Bacterial artificial chromosome


C-terminal of ROC


Genome-wide association study


Leucine-rich repeat kinase 2


Microtubule-associated protein tau


Parkinson’s disease


Ras of complex proteins


Single-nucleotide polymorphism



This research was supported entirely by the Intramural Research Program of the NIH and the National Institute on Aging.

Conflict of Interest

The author declares no conflicts of interest.


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© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Laboratory of NeurogeneticsNational Institute on Aging, National Institutes of HealthBethesdaUSA

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