Commentary (Research Highlights)

Author(s): Stephen D. Skaper

Journal Name: CNS & Neurological Disorders - Drug Targets
Formerly Current Drug Targets - CNS & Neurological Disorders

Volume 10 , Issue 1 , 2011

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Parkinsons Disease: Kinase Busters to the Rescue?

Parkinsons disease (PD) was first described in the essay entitled “An Essay of the Shaking Palsy” by James Parkinson in 1817. PD is the most common neurodegenerative movement disorder, whose neuropathological hallmarks are characterized by progressive and profound loss of neuromelanin-containing dopaminergic neurons in the substantia nigra pars compacta with the presence of eosinophilic intracytoplasmic, proteinaceous inclusions termed Lewy bodies and dystrophic Lewy neurites in surviving neurons. Although neuronal cell loss in the substantia nigra pars compacta is pronounced, there is widespread neurodegeneration in the CNS with the pars compacta being involved in midstages of the disease. Clinical manifestations of this complex disease include motor impairments involving resting tremor, bradykinesia, postural instability, gait difficulty and rigidity, along with non-motoric symptoms like autonomic, cognitive, and psychiatric problems. While the majority of PD cases are sporadic, ∼10% have been linked to mutations in specific genes, particularly the gene encoding leucine-rich repeat kinase 2 (LRRK2) in which the enzymes activity is increased. In vitro studies have also suggested a role for mutant forms of LRRK2 in neurotoxicity.

In a new study reported in Nature Medicine, Lee and colleagues have investigated the importance of these findings in vivo and identified LRRK2 kinase inhibitors that reduce neurotoxicity in mice. The authors first screened 84 commercially available kinase and phosphatase inhibitors for in vitro activity against LRRK2. Of these, eight compounds were found to decrease LRRK2 autophosphorylation. Their potency was similar against the wild-type enzyme and a mutated version (G2019S) that is a common cause of familial and sporadic PD. The compounds included an inhibitor of RAF1 (a kinase closely related to LRRK2) and indirubin-3-monooxime, an inhibitor of glycogen synthase kinase 3β. In cultured primary cortical neurons, over-expression of the G2019S mutant led to cell death. This effect was limited by the study compounds, but not by kinase inhibitors that do not block LRRK2 activity. Finally, the group devised a mouse model of LRRK2 toxicity in which the PD-linked mutant version of the protein was introduced via viral vector into the substantia nigra, the brain region most affected by PD. Peripheral injection of the test drugs decreased dopaminergic neuron loss caused by the transgene compared to injection of vehicle. Over-expression of wild-type LRRK2 or a kinase-dead form of the mutant enzyme did not have adverse effects.

Several of the molecules used by the Johns Hopkins team, including the indolinone GW5074 and indirubin-3-monooxime may be good starting points for drug development, given their high affinity for LRRK2. Whether or not the neuroprotective action of these compounds stems from the originally intended targets of many of the molecules, such as RAF1 and glycogen synthase kinase 3β, rather or in addition to LRRK2 inhibition, remains to be established. In addition, the in vivo model used in Lee et al. is based on over-expression of mutant LRRK2, which may create a bias toward showing a therapeutic effect for kinase inhibitors. Although this may not capture what goes on in PD patients, the model does feature degeneration of dopaminergic neurons. As with CNS drugs in general, selectivity, tolerability, and blood-brain barrier penetration present obstacles.

These caveats notwithstanding, the findings highlight a therapeutic potential for targeting aberrant LRRK2 kinase activity in PD, and could provide model to approach other genetic mutations that have been associated with this disorder.

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Article Details

Year: 2011
Page: [1 - 1]
Pages: 1
DOI: 10.2174/187152711794488593

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