TY - JOUR
T1 - Somatic mutations in neurons during aging and neurodegeneration
AU - Verheijen, Bert M.
AU - Vermulst, Marc
AU - van Leeuwen, Fred W.
PY - 2018/6/1
Y1 - 2018/6/1
N2 - The nervous system is composed of a large variety of neurons with a diverse array of morphological and functional properties. This heterogeneity is essential for the construction and maintenance of a distinct set of neural networks with unique characteristics. Accumulating evidence now indicates that neurons do not only differ at a functional level, but also at the genomic level. These genomic discrepancies seem to be the result of somatic mutations that emerge in nervous tissue during development and aging. Ultimately, these mutations bring about a genetically heterogeneous population of neurons, a phenomenon that is commonly referred to as "somatic brain mosaicism". Improved understanding of the development and consequences of somatic brain mosaicism is crucial to understand the impact of somatic mutations on neuronal function in human aging and disease. Here, we highlight a number of topics related to somatic brain mosaicism, including some early experimental evidence for somatic mutations in post-mitotic neurons of the hypothalamo-neurohypophyseal system. We propose that age-related somatic mutations are particularly interesting, because aging is a major risk factor for a variety of neuronal diseases, including Alzheimer's disease. We highlight potential links between somatic mutations and the development of these diseases and argue that recent advances in single-cell genomics and in vivo physiology have now finally made it possible to dissect the origins and consequences of neuronal mutations in unprecedented detail.
AB - The nervous system is composed of a large variety of neurons with a diverse array of morphological and functional properties. This heterogeneity is essential for the construction and maintenance of a distinct set of neural networks with unique characteristics. Accumulating evidence now indicates that neurons do not only differ at a functional level, but also at the genomic level. These genomic discrepancies seem to be the result of somatic mutations that emerge in nervous tissue during development and aging. Ultimately, these mutations bring about a genetically heterogeneous population of neurons, a phenomenon that is commonly referred to as "somatic brain mosaicism". Improved understanding of the development and consequences of somatic brain mosaicism is crucial to understand the impact of somatic mutations on neuronal function in human aging and disease. Here, we highlight a number of topics related to somatic brain mosaicism, including some early experimental evidence for somatic mutations in post-mitotic neurons of the hypothalamo-neurohypophyseal system. We propose that age-related somatic mutations are particularly interesting, because aging is a major risk factor for a variety of neuronal diseases, including Alzheimer's disease. We highlight potential links between somatic mutations and the development of these diseases and argue that recent advances in single-cell genomics and in vivo physiology have now finally made it possible to dissect the origins and consequences of neuronal mutations in unprecedented detail.
KW - Somatic mutations
KW - Genome integrity
KW - Somatic brain mosaicism
KW - Neuronal development
KW - Aging
KW - Neurological disorders
KW - Neurodegeneration
KW - HOMOZYGOUS BRATTLEBORO RAT
KW - SOLITARY MAGNOCELLULAR NEURONS
KW - CEREBRAL AMYLOID ANGIOPATHY
KW - ALZHEIMERS-DISEASE PATIENTS
KW - FOCAL CORTICAL DYSPLASIA
KW - HUMAN BRAIN-DEVELOPMENT
KW - COPY-NUMBER VARIATION
KW - DOUBLE-STRAND BREAKS
KW - SINGLE-CELL
KW - IN-VIVO
U2 - 10.1007/s00401-018-1850-y
DO - 10.1007/s00401-018-1850-y
M3 - (Systematic) Review article
C2 - 29705908
SN - 0001-6322
VL - 135
SP - 811
EP - 826
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 6
ER -