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  • Review Article
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Modelling brain diseases in mice: the challenges of design and analysis

Nature Reviews Genetics volume 4, pages 296–307 (2003)Cite this article

Key Points

  • Genetically engineered mouse models have given us insights into the molecular pathogenesis of several neurological diseases. However, often they fail to accurately replicate all, or even most, of the features of the human disease. Nonetheless, careful analysis of the existing models points to the reasons for this failure.

  • It is necessary to accelerate the disease process to model the dominantly inherited neurodegenerative diseases within the normal lifespan of a mouse. Transgenic mice that overexpress the mutant proteins under potent heterologous promoters reproduce disease-like phenotypes; however, such models often display features that are a result of abnormal expression.

  • To generate accurate models for polyglutamine diseases, a knock-in strategy that targets long repeats that are predicted to cause infantile disease in humans is a valid approach as it eliminates the confounding effects of overexpression.

  • Reproducing the clinical and pathological features of diseases caused by missense and/or splicing mutations, such as α-synuclein-related Parkinson disease or tauopathy, is a challenge. The creation of a large collection of BAC- or YAC-based trangenics is worthy of consideration.

  • Generating faithful animal models for recessive diseases can not always be achieved through the conventional knockout approaches. Conditional gene disruption, or partial rescue of the knockout allele, might be necessary to model those diseases that are caused by insufficient levels or dysfunction of the protein.

  • The effects of skewed X-chromosome inactivation might complicate the phenotypic analysis of mouse models of X-linked disorders. Modelling an X-linked male-lethal disease can be also challenging since most ES cell lines are derived from the male germline.

  • Progress in manipulating the mouse genome, together with the development of new behavioural assays and imaging technologies, will markedly change the approaches to generating and analysing mouse models of brain diseases in the near future.

Abstract

Genetically engineered mice have been generated to model a variety of neurological disorders. Several of these models have provided valuable insights into the pathogenesis of the relevant diseases; however, they have rarely reproduced all, or even most, of the features observed in the corresponding human conditions. Here, we review the challenges that must be faced when attempting to accurately reproduce human brain disorders in mice, and discuss some of the ways to overcome them. Building on the knowledge gathered from the study of existing mutants, and on recent progress in phenotyping mutant mice, we anticipate better methods for preclinical interventional trials and significant advances in the understanding and treatment of neurological diseases.

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Figure 1: Pathogenic mechanisms in motor neuron diseases.

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Authors and Affiliations

  1. Department of Molecular and Human Genetics and Howard Hughes Medical Institute, Baylor College of Medicine, 1 Baylor Plaza, Houston, 77030, Texas, USA

    Kei Watase & Huda Y. Zoghbi

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  1. Kei Watase
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Correspondence to Huda Y. Zoghbi.

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Databases

LocusLink

α4-nAChR

AR

ataxin-1

frataxin

Frda

FRDA

Fmr1

FMR1

Fmr2

FMRP

Gdi1

Hprt

HPRT

Huntingtin

Mecp2

MeCP2

MECP2

Pcp2

Sca1

SCA1

SMA

Smn

SMN1

SMN2

Sod1

Ube3a

UBE3A

OMIM

α-synuclein

adrenoleukodystrophy

amyotrophic lateral sclerosis

Alzheimer disease

Angelman syndrome

cystic fibrosis

dentatorubral pallidoluysian atrophy

fragile X syndrome A

Fabry disease

Friedreich ataxia

Huntington disease

incontinentia pigmenti

Lesch-Nyhan syndrome

Lissencephaly

microphthalmia with linear skin defects

Niemann-Pick disease

Parkinson disease

progressive myoclonus epilepsy

Rett syndrome

SCA1

SCA2

SCA6

SCA7

spinobulbar muscular atrophy

X-linked lissencephaly

Further information

Mouse Genome Informatics

TBASE

Glossary

LEWY BODIES

Intracytoplasmic enosinophilic round-to-elongated inclusions that are found in injured neurons. The Lewy body is a histological marker in Parkinson disease.

HETEROLOGOUS PROMOTER

A DNA sequence that drives the transcription of a non-endogenous target gene that is placed in its adjacent region.

CEREBELLUM

The part of the vertebrate hindbrain that modulates the force and range of movements, maintains balance and is involved in motor learning.

BRAIN STEM

The portion of the brain between the cerebrum and the spinal cord, comprising the mesencephalon, pons and medulla.

PURKINJE CELLS

The cerebellar neurons that convey the output signals of the cerebellar cortex.

ACONITASES

The enzymes that catalyse the reversible hydration of cis-aconitase to yield citrate or isocitrate. They are involved in the citric acid cycle.

DENERVATION

The removal of the nerve supply to a tissue.

CRE-LOXP RECOMBINATION SYSTEM

A tool for tissue-specific knockout. It uses Cre recombinase from bacteriophage P1, which mediates intra- and intermolecular site-specific recombination between loxP sites.

DYSTROPHIC

Cells or tissues that are undergoing progressive changes that might result from denervation or defective energy supply.

DYSMORPHIC

A body characteristic that is abnormal as the result of a developmental defect.

MACROORCHIDISM

The state of having abnormally large testes.

ENCEPHALOPATHY

Altered cerebral function as a result of diffuse pathology.

NESTIN-CRE TRANSGENE

A type of transgene, in which Cre recombinase is expressed in a neuronal lineage under the control of the nestin promoter.

HYPOMORPHIC ALLELE

An allele that expresses a gene product with reduced activity.

GYRI

The crests of convolutions in the cerebral cortex.

CORTICAL LAYERING

The formation of six histologically identifiable layers in the cerebral cortex.

NEURONAL HETEROTOPIAS

The displacement of neurons.

PGK-NEO CASSETTE

A gene cassette that contains a neomycin-resistant gene under the control of the phosphoglycerol kinase gene promoter.

ANTINOCICEPTIVE

Reduces the sensitivity to painful stimuli.

FEBRILE SEIZURE PLUS

A syndrome in which patients have febrile seizure, plus an additional seizure subtype in adulthood.

CHANNELOPATHIES

Diseases that are caused by defective ion-channel proteins.

CEREBRAL ISCHAEMIA

A deficiency in the blood supply to the brain.

HAEMODYNAMIC RESPONSES

The changes in blood flow, blood volume and blood oxygenation that occur in response to local neural activity.

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Watase, K., Zoghbi, H. Modelling brain diseases in mice: the challenges of design and analysis. Nat Rev Genet 4, 296–307 (2003). https://doi.org/10.1038/nrg1045

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