# Mechanisms of motor superperformance

> **NIH NIH R56** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $539,677

## Abstract

MECHANISMS OF MOTOR SUPERPERFORMANCE: ABSTRACT
Clinical experience and world population-level data indicate that most neurological disability stems from motor
dysfunction. Yet, spontaneous superperformer mutations occur in a variety of species including man,
illustrating that the intrinsic motor capacity of the organism can be augmented. We set out to identify similar
mutations by rotarod screening of 33,806 laboratory mice harboring chemically induced random mutations with
the goal of mechanistically explaining and, eventually, pharmacologically enabling the phenomenon of motor
superperformance. In this context, we have discovered that a mutation in an unsuspected gene, Rif1
(Replication Timing Regulatory Factor 1), confers supernormal motor ability. Using clustered regularly
interspaced short palindromic repeats (CRISPR) Rif1-mutant mice, we have determined that: 1) mutant
superperformance is a selective phenotype, with distinct changes in motor features quantifiable by our novel
analysis method, but no other effects upon rigorous behavioral testing, and 2) the mutation also leads to
accelerated motor recovery from stroke. The superperformance mechanism, however, is unknown: although
Rif1 participates in DNA repair and in transcriptional regulation via G4 folded DNA structural stabilization, little
is known about its function in the nervous system. There is precedent that DNA repair may be associated to
synaptic transmission strength, while DNA G4 regulation could enhance the transcription of genes active in the
motor system. We have refined this hypothetical framework by identifying several consequences of the Rif1
mutation: a) Increased cerebellar Purkinje cell firing regularity and local field potential changes in the non-
moving mouse, which can influence movement precision, with change of these neurophysiological parameters
upon locomotion on a treadmill; b) Increased resistance to DNA-damaging radiation; c) Increased resistance to
G4 stabilization; d) Overexpression of a fraction of the cerebellar (but not forebrain or spinal cord) synaptic
transcriptome including potential Rif1 mutation mediators such as Kcnma1, Kif5c and Nab2; e) These
transcripts may be relevant to the phenotype because we show that loss of function mutations in them degrade
motor performance, whereas f) Cerebellar injection of adenovirus-containing Nab2 induces superperformance.
This proposal unifies this body of work by postulating that the Rif1 mutation modifies DNA repair and/or G4
DNA folding resulting in upregulation of synaptic transcripts, with either one or both mechanisms augmenting
the precision of cerebellar synapse activity relevant to movement control. To this effect, we will conduct
neurophysiological studies, determine the transcriptome in single cells, alter Kcnma1, Kif5c and Nab2
expression, and investigate DNA repair and DNA G4 regulation to test which of these mechanisms enable the
superperformance phenotype. Our goal is to initiate and steer the me...

## Key facts

- **NIH application ID:** 10701427
- **Project number:** 1R56NS121993-01A1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Juan M. Pascual
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $539,677
- **Award type:** 1
- **Project period:** 2022-09-21 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10701427

## Citation

> US National Institutes of Health, RePORTER application 10701427, Mechanisms of motor superperformance (1R56NS121993-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10701427. Licensed CC0.

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