Stuart J. Grice, Ji-Long Liu
Developmental motifs in neurodegeneration:Neurodegeneration, the prominent feature of neurodegenerative disease, is characterized by the progressive and selective loss of neuronal function. As some of the pathologies caused by neurodegeneration may be irreversible, early intervention will be required for the treatments that aim to slow or halt the manifestation of these diseases. Traditionally, neurodegeneration evokes the idea of a progressive decline of brain function, which ultimately ends with the loss of cognitive, sensory, or motor ability, and the death of specific neuronal subtypes. However, it is now starting to emerge that some neurodegenerative diseases may be caused, or at least become primed, by defects that arise during neurodevelopment.
The discovery of these critical neurodevelopmental windows, which occur prior to a pronounced loss of nerve function, highlights the need to understand how altered neurodevelopmental processes could sensitize nerve cells to become susceptible to degeneration later in life (Hickman et al., 2022). Interestingly, neurodevelopmental and neurodegenerative disorders share many overlapping molecular mechanisms, and some causative genes (Schor and Bianchi, 2021). Defects in ribonuclear protein processing, protein aggregation, mitochondrial function, synaptic function, stem cell proliferative capacity, and neuronal morphology are observed to varying degrees in neurodevelopmental conditions, such as intellectual disability and autism spectrum disorders, and in degenerative disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease (HD), motor neuron disease, and spinal muscular atrophy (SMA) (Groen et al., 2018; Hickman et al., 2022).
To understand neurodegenerative disease, it is important to identify the molecular and physiological changes that emerge throughout the lifespan of model organisms and patients.Furthermore, it will be essential to characterize how these defects could cause the selective loss, or dysfunction, of neuronal subtypes. In this perspective, we look at current research into the mechanisms of SMA and HD that highlight how developmental abnormalities can predispose nerve cells to degeneration. We then propose ideas on how this research may be broadly applicable to other neurological diseases.
Developmental onset of SMA:SMA is a common autosomal recessive neurodegenerative disease and is characterized by spinal motor neuron loss, impaired motor function, and, often, premature death. SMA is caused by mutations and deletions in the widely expressed survival motor neuron 1 (SMN1) gene, which encodes for the survival motor neuron protein (SMN). Humans also carry a second gene,SMN2, which is almost identical toSMN1. However, a point mutation inSMN2affects the splicing of its transcript, and only low levels of mature SMN protein are produced by the gene. The chromosomal region that contains theSMNloci is somewhat labile, and patients can have multiple copies ofSMN2. This gives rise to varying levels of SMN protein, generating a broad range of disease severities and onset timings, which can vary from a few months up until early adulthood (Groen et al., 2018).
SMA is classically defined as a degenerative disease, suggesting the pathology will be caused by the loss of SMN function in mature neurons. Notwithstanding, SMN protein is required during the setup of the embryonic and the early postnatal nervous systems (Grice and Liu, 2011; Groen et al., 2018). Furthermore, whilst SMN is essential for motor neuron survival, reducing SMN levels in motoneuronal progenitors is sufficient to cause SMA-like phenotypes in animal models. Finally, with highly promising therapies currently being assessed, the broad consensus highlights that the early administration of therapeutics will result in the best patient outcomes (Groen et al., 2018).
Extending our knowledge around the neurodevelopmental origination of SMA, findings have now highlighted the potential importance of neuronal stem cells in its pathology. SMN is widely expressed, and protein loss occurs in all tissues and cell types in patients. In a recent paper by Grice and Liu, SMN manipulation was restricted to the neuronal stem cells (neuroblasts) and the immature neuroblast progeny, which had not fully differentiated or formed synapses (Grice and Liu, 2022). To achieve this, SMN knockdown and rescue studies were performed during the waves of proliferation in wild-typeDrosophilaand a fly model of SMA, respectively. Using the neuroblast-specific GAL4 divers in combination with a GAL80 repression system (which reduces transient expression), SMN expression and knockdown were switched on in, and restricted to,Drosophilaneuroblasts (Grice and Liu, 2022). When SMN knock-down was targeted specifically to neuroblasts in the embryonic and larval stages, locomotor and movement defects were present in the adult, even though SMN levels at this point were returned to normal. Targeted rescue, which involved expressing SMN in the neuroblast populations ofSmnnull mutants, improved locomotor function and extended the life span of the larvae. In contrast, knock-down targeted to specific differentiated neuronal populations, such as the motor neurons and interneurons, yielded little effect. Overall, this work highlighted SMN expression during the period of neurodevelopment that precedes the formation of synapses is essential for the long-term function of theDrosophilanervous system.
More broadly, SMA models show defects in proliferative pathways, morphological changes in the dividing cells in the ventral horn, and the untimely differentiation of neurons (Grice and Liu, 2011; Chang et al., 2015; Grice and Liu, 2015; Groen et al., 2018). Taken together, these studies highlight the role of SMN in the fidelity of neurogenesis and show that low levels of SMN protein can cause defects in neuronal differentiation and maturation. This, of course, does not suggest that additional sensitivities do not arise in differentiated neurons. Many of the genes linked to monogenic neurodegeneration display pleiotropy, or the associated proteins have many assigned functions. This functional heterogeneity could lead to a palette of mechanisms that ultimately impact the severity of the disease phenotypes. SMN protein functions in the modulation of post-transcriptional gene regulation, including the assembly of the ribonuclear protein classes that underpin splicing, mRNA transport, ribosomal biogenesis, and translational control (Grice and Liu, 2015; Groen et al., 2018). These processes may guide developing neurons to adopt diverse receptor profiles, neurotransmitter identities, and the unique morphologies that are required for a functional nervous system. In turn, they are also essential for the maintenance and control of synaptic integrity and synaptic plasticity in differentiated neurons. It is therefore plausible that the neurodegeneration of the neurons observed in SMA may manifest from both impaired neuronal development and inefficient neuronal homeostasis.
Developmental manifestation of Huntington’s disease:HD is caused by a pathogenic CAG trinucleotide repeat in the huntingtin gene, which leads to an abnormally long polyglutamine tract in the huntingtin protein (Bates et al., 2015). Like SMA, HD has the hallmarks of a neurodegenerative disease, with the associated chorea generally developing at around 30–50 years of age. Notwithstanding, more subtle neuropsychological phenotypes, relating to cognitive and emotional processing, can be detected much earlier (Bates et al., 2015), and in children carrying the mutant CAG trinucleotide, slower brain growth can be observed (Nopoulos et al., 2011). Furthermore, HD mouse models and patients display some neurogenesis defects, and abnormalities in both neuronal migration and maturation have been reported (Hickman et al., 2022). Defects in axon growth are also apparent in HD models, leading to decreased axonal trajectories across the hemispheres of the corpus callosum (Capizzi et al., 2022). This reduced axonal expansion is associated with the reduction of nuclear mitotic apparatus protein 1 (NUMA1), a protein that aids the formation and organization of the mitotic spindle, and the microtubule networks in growth cones (Capizzi et al., 2022).
As with SMN, the wild-type Huntingtin protein has many assigned functions, such as those linked to mitotic spindle assembly, organelle trafficking, and axonal transport (Bates et al., 2015). It is therefore again plausible that the neurodegeneration of the neurons observed in HD may manifest from both impaired axonal outgrowth and perturbed neuronal function.
Critical windows in the development of neurodegenerative diseases:Understanding the long-term trajectories of neurodegenerative disease will enable the identification of novel molecular mechanisms, which will ultimately facilitate the design of therapies that slow or halt these terrible conditions. Notwithstanding, the aetiologies of many neurodegenerative diseases are more complex than the monogenic conditions described in this perspective, with numerous interacting genetic and external drivers promoting disease susceptibility. However, deciphering the mechanisms that underpin the monogenetic forms of neurodegenerative conditions, such as SMN and HD, will offer an understanding into the molecular mechanisms that cause neurons to become susceptible to premature decline and dysfunction. By combining our knowledge from the spectrum of neurodevelopmental (such as intellectual disability, and autism spectrum disorders) and neurodevelopmental diseases (such as Alzheimer’s disease, Parkinson’s disease and motor neurone disease), we can identify the overlapping and unique features of the different diseases and susceptible neuronal types (Schor and Bianchi, 2021).
When understanding the impact of neurodevelopment in these conditions, it is important to encompass the whole natural history of the nervous system, from fetal neurogenesis through to the maturation processes that occur in early adult life, and beyond (Hickman et al., 2022; Figure 1). Mechanistically, the neurodevelopmental component of neurodegeneration may be primed by multiple factors. Firstly, this may occur at the stem cell level, where stem cells may be lost, or regions of the brain may be subject to over or under proliferation. Secondly, after dividing, neurons commit to a lineage by adopting distinct transcriptional identities. These metastable identities ultimately control the morphological and functional maturation of the neuron. The understanding of how subtle but ultimately deleterious alterations in cellular identities can cause disease is in its infancy; however, defects in the maturation of neurons can be seen across a number of neurological diseases. In addition, altered neuronal identity could have downstream impacts on neuronal migration and synaptogenesis. Furthermore, subtle changes in the establishment of neuronal networks, suboptimal receptor profiles, and altered neurotransmitter identities, may all lead to detrimental alterations in neuronal physiology over time.
Figure 1|Defective developmental processes may prime neurons to degenerate.
Finally, in addition to genetic etiology, environmental risk factors will likely magnify the neurodevelopmental changes that enhance an individual’s susceptibility to neurodegeneration. It may be that district development windows exist where the nervous system is more susceptible to environmental insult. Poor diet, inactivity, and environmental toxins can increase an individual’s vulnerability to neuroinflammation or suboptimal growth (Verdile et al., 2015; Heffernan and Hare, 2018), and conditions such as type-2 diabetes and obesity will enhance the inflammatory and metabolic stresses on the nervous system (Verdile et al., 2015). It is therefore essential to not only map the natural history of each neurodegenerative disease but also to understand the unique genetic backgrounds and environmental contexts each disease case has been subjected to.
*Correspondence to:Stuart J. Grice, DPhil, stuartjfgrice@gmail.com; Ji-Long Liu, PhD, jilong.liu@dpag.ox.ac.uk or liujl3@shanghaitech.edu.cn.
https://orcid.org/0000-0003-2944-6076 (Stuart J. Grice)
https://orcid.org/0000-0002-4834-8554 (Ji-Long Liu)
Date of submission:November 3, 2022
Date of decision:November 25, 2022
Date of acceptance:December 23, 2022
Date of web publication:January 30, 2023
https://doi.org/10.4103/1673-5374.367844
How to cite this article:Grice SJ, Liu JL (2023) Neurodevelopmental defects as a primer of neurodegeneration: lessons from spinal muscular atrophy and Huntington’s disease. Neural Regen Res 18(9):1952-1953.
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