# The Effect of Parkinson's-linked LRRK2-G2019S Mutation on Corticostriatal-based Cognition

> **NIH NIH F31** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $43,920

## Abstract

Project Summary
Parkinson’s disease (PD) is a progressive neurodegenerative disorder symptomatically characterized by motor
dysfunctions caused by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc).
However, many years prior to the onset of clinical motor symptoms, non-motor symptoms (NMS) such as
cognitive deficits in executive processes that control goal-directed behavior, cognitive flexibility, and
attention can be present. The causes of non-motor symptoms are not known, and while current PD treatments
address dopamine deficiencies and motor symptoms, treatment with levodopa, the most common therapy for
alleviating motor symptoms, has been shown to exacerbate cognitive impairments. The most common PD-
linked mutation is the G2019S mutation in leucine-rich repeat kinase 2 (LRRK2), which causes autosomal-
dominant PD with substantial similarity to idiopathic PD in terms of disease progression, suggesting common
disease mechanisms. LRRK2 expression in the striatum peaks during early postnatal life coincident with the
establishment of corticostriatal circuitry. Previous work in the lab has shown that G2019S-LRRK2 alters
structural and functional development of corticostriatal circuits and abolishes corticostriatal LTP. This suggests
that mutant LRRK2 may derail circuit development during a critical period when corticostriatal connectivity is
highly sensitive to changes in network activity. This in turn suggests that such abnormal activity and loss of
bidirectional plasticity could permanently affect striatal circuit function and behaviors such circuits support.
Accordingly, I hypothesize that aberrant striatal synaptic plasticity and activity during development would impair
cognitive functions mediated by corticostriatal circuitry. This proposal addresses the hypothesis by comparing
the performance of G2019S-LRRK2 knockin and wild type young adult mice on executive tasks shown to be
impaired in early-stage PD such as goal-directed learning, cognitive flexibility, and attention using a Bussey-
Saksida mouse touchscreen system. Additionally, I will test whether early, in vivo intervention with a selective
LRRK2 kinase inhibitor, MLi-2, can normalize the transient aberrant synaptic activity, thus preventing
behavioral deficits later in life.

## Key facts

- **NIH application ID:** 9992371
- **Project number:** 1F31NS117089-01
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** AYAN HUSSEIN
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $43,920
- **Award type:** 1
- **Project period:** 2020-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9992371

## Citation

> US National Institutes of Health, RePORTER application 9992371, The Effect of Parkinson's-linked LRRK2-G2019S Mutation on Corticostriatal-based Cognition (1F31NS117089-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9992371. Licensed CC0.

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