Induced pluripotent stem cell-derived and directly reprogrammed neurons to study neurodegenerative diseases: The impact of aging signatures

Abstract

Many diseases of the central nervous system are age-associated and do not directly result from genetic mutations. These include late-onset neurodegenerative diseases (NDDs), which represent a challenge for biomedical research and drug development due to the impossibility to access to viable human brain specimens. Advancements in reprogramming technologies have allowed to obtain neurons from induced pluripotent stem cells (iPSCs) or directly from somatic cells (iNs), leading to the generation of better models to understand the molecular mechanisms and design of new drugs. Nevertheless, iPSC technology faces some limitations due to reprogramming-associated cellular rejuvenation which resets the aging hallmarks of donor cells. Given the prominent role of aging for the development and manifestation of late-onset NDDs, this suggests that this approach is not the most suitable to accurately model age-related diseases. Direct neuronal reprogramming, by which a neuron is formed via direct conversion from a somatic cell without going through a pluripotent intermediate stage, allows the possibility to generate patient-derived neurons that maintain aging and epigenetic signatures of the donor. This aspect may be advantageous for investigating the role of aging in neurodegeneration and for finely dissecting underlying pathological mechanisms. Here, we will compare iPSC and iN models as regards the aging status and explore how this difference is reported to affect the phenotype of NDD in vitro models.

CRISPRi: a way to integrate iPSC-derived neuronal models

“…Significantly, iPSC-derived neurons from patients maintain their genetic background and disease-causing mutations, making them important models for understanding genetic contributions to disease in specific cellular subtypes of interest such as in Parkinson's disease (PD) [ 42–47 ], Alzheimer's disease (AD) [ 48 ], Huntington's disease (HD) [ 49 ], spinal muscular atrophy [ 50 ], amyotrophic lateral sclerosis (ALS) [ 40 , 51 ] and neurological disorders such as autism spectrum disorder [ 52 ], Rett syndrome [ 53 ] and schizophrenia [ 54 ]. Importantly, iPSC reprogramming may reset crucial ageing signatures such as epigenetic memory and metabolic ageing, implicating the translatability of iPSC-derived neurons to age-related neurodegenerative disease, compared with directly induced neurons (reviewed in [ 55 , 56 ]).…”

Preservation of an Aging-Associated Mitochondrial Signature in Advanced Human Neuronal Models

“…The effectiveness of treatment strategies predicted by animal experiments remains controversial due to their failure to translate to clinical investigation, especially on disease-related levels [17, 18]. In general, the research and development of pharmaceutical interventions targeting aging and neurodegenerative illnesses pose significant challenges due to the limited availability of healthy, viable human neuronal cells [19]. In recent years, new approaches have emerged for generating neuronal cells, such as through nuclear reprogramming of somatic cells [20, 21].…”

Parallel neurodegenerative phenotypes in sporadic Parkinson’s disease fibroblasts and midbrain dopamine neurons

“…Importantly, these cells are known to maintain the age and epigenetic signatures of the patient, thus capturing the aging and environmental history, which are the biggest risk factors for PD ( Auburger et al, 2012 ; Ivanov et al, 2016 ; Teves et al, 2017 ). In contrast, due to reprogramming, iPSCs are known to revert to a ‘younger state’ mostly devoid of aging markers ( Aversano et al, 2022 ; Mertens et al, 2018 ). Thus, iPSCs and their neural progeny, such as DA neurons, may mainly convey mechanisms of early neural vulnerabilities in PD such as the influences of potential genetic variants.…”