# Mechanisms of Motor Superperformance

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $566,625

## 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 persons and animals, illustrating
that the intrinsic motor capacity of the organism can be augmented. We set out to identify similar mutations by
rotarod screening of 32,726 laboratory mice harboring chemically induced random mutations with the goal of
mechanistically explaining motor superperformance. In this context, we have discovered that a point mutation in
an unsuspected gene, Rif1 (Replication Timing Regulatory Factor 1), converts a single mouse residue to the
primate one and confers supernormal motor ability. Using clustered regularly interspaced short palindromic
repeats (CRISPR) Rif1-mutant mice, we have determined that this superperformance is a motor-selective
phenotype manifest upon several motor tasks but devoid of other effects upon various rigorous behavioral and
longevity analyses. Rif1-mutant mice also exhibit enhanced recovery from stroke in the motor cerebral cortex.
The superperformance mechanism 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 with synaptic transmission strength, while DNA G4
regulation could enhance the transcription of genes active in the motor system. We have strengthened this
hypothetical framework by identifying several consequences of the Rif1 mutation: a) Altered Purkinje cell firing
regularity and local field potential changes in mouse cerebellum, which can influence movement precision, with
change of these neurophysiological parameters upon locomotion on a treadmill; b) Increased cellular resistance
to DNA-damaging radiation; c) Increased cell 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
their loss of function degrades motor performance, whereas f) Cerebellar injection of adenovirus-containing Nab2
induces superperformance. Thus, we will expand current cerebellar learning conceptions by postulating that the
Rif1 mutation facilitates DNA repair and/or loosens G4 DNA folding leading to upregulation of synaptic
transcripts, with either one or both mechanisms modifying the range or precision of cerebellar synapse activity
that underlies movement control. To this effect, we will conduct neurophysiological studies, study the function of
native RIF1, manipulate Nab2, Kcnma1 and Kif5c expression levels, and investigate DNA repair and DNA G4
regulation to test which of these mechanisms enable the superperformance phenotype. We will also investiga...

## Key facts

- **NIH application ID:** 10881494
- **Project number:** 1R01NS133439-01A1
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Juan M. Pascual
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $566,625
- **Award type:** 1
- **Project period:** 2024-09-18 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881494

## Citation

> US National Institutes of Health, RePORTER application 10881494, Mechanisms of Motor Superperformance (1R01NS133439-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10881494. Licensed CC0.

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