1 Introduction

Converging evidence suggests that brain structure alterations may proceed overt cognitive impairment or motor disability in neurodegenerative diseases by several decades. Magnetic resonance imaging measurements of white matter myelin water fraction and gray matter volume in healthy infant carriers and noncarriers of the apolipoprotein E (APOE) ε4 allele demonstrates some of the earliest brain changes associated with the genetic predisposition to Alzheimer's disease (AD) [1, 2]. The measures of growth are abnormal in child and adolescent carriers of mHTT, decades before Huntington's disease (HD) onset [3]. Neocortical sulcal measures indicate coexistence of abnormal neurodevelopmental and neurodegenerative processes in HD [4]. Lower intracranial volume in subjects with prodromal HD compared with controls lends support to the theory that abnormal brain development may be a precursor to neurodegeneration in HD [5]. Thus, Mehler and Gokhan propose that neurodegenerative diseases originate from abnormal brain development and are atypical neurodevelopmental disorders [6].

Recently, increasing number of studies has begun to focus on exploring the developmental mechanisms in neurodegenerative diseases. Although AD is considered to be an aging-related neurodegenerative disorder, the most common used animal model 5XFAD mice express mutant forms of APP/PS1 throughout the life span. Disrupted maturation of prefrontal Layer 5 neuronal circuits were detected in 5XFAD mice [7], indicating early developmental defects of cortical circuits may contribute to the age-dependent synaptic pathology and neurodegeneration later in life. In a study of spinal cerebellar ataxia, overexpression of mutant ATXN1 protein in a mouse model stimulated the proliferation of stem cells in the developing cerebellum and excessive differentiation into GABAergic inhibitory neurons, leading to functional disruption of Purkinje cells and causing cerebellar impairment resulting in ataxia [8]. In one research on Parkinson's syndrome, homozygous mutations in DNAJC6 could lead to widespread neurodevelopmental defects, including impairments in dopaminergic neurons and functional disturbances in ventral midbrain-like organ structures, as observed in the creation of induced iPSCs and brain-like organ models [9]. Research utilizing mouse embryonic models and human fetal tissues in studies of HD has shown that HD impacts neurodevelopment, specifically inducing defects in neuroepithelial cell junctions, disrupting interkinetic nuclear migration (INM), and altering the cell cycle [10]. In addition, HTT protein is required for multipolar bipolar conversion and projection neuron migration, loss of HTT during embryonic period affects morphology of adult neurons [11]. Nonetheless, mouse studies show that either expressing mHTT or depleting wild-type (WT) HTT for only 2–3 weeks after birth is sufficient for the mice to later develop the hallmark features of HD pathology [12]. Therapeutic effects on sensory, motor, and cognitive functions can be observed and preserved in HD adult mice when GABA receptor agonist pharmacological interventions are administered to HD neonatal mice [13]. More importantly, selective expression of mutant huntingtin during development recapitulates characteristic features of Huntington's disease. Taken together, numerous proteins, which are hypothesized to be crucial in the progression of neurodegeneration, exert either direct or indirect influences on the development of the central nervous system.

Hereditary spastic paraplegia (HSP), also known as familial spastic paraparesis (SPG), refers to a group of inherited disorders that characterized by spastic paraplegia of the lower limbs [14]. Some patients may also experience other neurological symptoms, such as ataxia, muscle spasm, urinary incontinence, and intellectual impairment. Clinically, HSP/SPG can be divided into pure and complex types. Pure HSP mainly characterized by slowly progressive spastic weakness of the lower limbs and spasticity. Complicated HSP is associated with additional neurologic symptoms, including mental retardation, epilepsy, multiple psychiatric disorders, retinal dysfunction, etc. In most cases, pure HSP shows autosomal dominant (AD) or X-linked and complicated HSP shows autosomal recessive (AR) inheritance [15]. Currently, only a limited number of HSP types, such as SPG3A/ATL1, SPG7/PGN, SPG9/ALDH18A1, SPG18/ERLIN2, SPG30/KIF1A, SPG58/KIF1C, and SPG72/REEP2, have been demonstrated to exhibit both AD and AR patterns of inheritance. Interestingly, a recent study revealed that the p.V168M mutation in ERLIN2 leads to a phenoconversion, manifesting as amyotrophic lateral sclerosis (ALS) in the second generation, pure HSP in the third generation, and complicated form of HSP in the fourth generation [16]. Therefore, there exists a complex mechanism underlying the multifaceted nature of certain types of HSPs.

HSP exhibits a high degree of heterogeneity, encompassing a diverse array of genetic subtypes, and is characterized by substantial variations in both the age of onset and clinical manifestations [17]. Although HSP was considered as a neurodegenerative disorder, it can present in neonatal, infancy, childhood, adolescence, or adulthood. Thus, it is crucial to understand the early developmental mechanisms associated with HSP, which will facility to identify the best targets and approaches toward this disease. Here we summarized the clinical phenotypes, expression trajectory, and protein functions of HSP from the perspective of neurodevelopment. We believe that the studies of neurodevelopmental implications of HSP will provide a new perspective on the pathogenesis of this disease.

2 The Clinical Features and Neocortical Morphometry Highlights the Presence of Brain Developmental Phenotypes in HSP

The genetic background of HSP is complex, which related to the type and location of gene mutations. According to the Online Human Mendelian Inheritance Database (OMIM), 89 spastic paraplegia gene (SPG) subtypes and 76 causing genes of HSP have been identified (Tables S1 and S2). We analyzed the clinical phenotypes of the 89 identified subtypes and discovered that 14.29% subtype of HSP patients with symptoms earliest reported on neonatal (from birth to up to 6 months), 37.14% subtype of HSP with symptoms earliest reported on infancy (birth to 2 years old), or on childhood (3–11 years old), and only 5.71% subtype of HSP with symptoms earliest reported on adolescents (12–18 years old) or adult (older than 18 years old) [18]. Moreover, until now over 35% HSP subtypes were reported exhibiting developmental abnormalities, such as microcephaly, corpus callosum agenesis defect, ventricular enlargement, and cerebellar hypoplasia (Table S1 and Figure 1).

3 Expression Trajectories of HSP Genes in Developing Brains

To better track the expression profiles of the genes responsible for HSP, we investigate gene expression of 73 HSP causing genes in the cortex across pre-natal and postnatal periods from BrainSpan data (http://www.brainspan.org/). We summarized the expression profiles and found that 23/73 genes have higher expression in late developmental stage (after 6 months of gestation) and after birth, whereas 50/73 genes have higher expression in early development (before 26 weeks of gestation). Among these 50 genes, 26 genes (highlighted in yellow in Figure 2A) exhibit high level during embryonic periods, with their expression subsequently decreasing after birth. Conversely, the remaining 24 genes (highlighted in blue in Figure 2A) display minimal differences in expression between the embryonic and adult periods. Genes that are highly expressed during the embryonic period are prone to being associated with developmental disorders. For example, genes including SPG1/L1CAM, SPG47/AP4B1, SPG50/AP4M1, SPG51/AP4E1, and SPG61/ARL6IP, that caused ventricular enlargement were highly expressed during embryonic period. All of the genes associated with microcephaly or cerebellar hypoplasia, except for AMPD2/SPG63, were highly expressed during the embryonic period. In addition, 63.15% of the genes associated with agenesis of corpus callosum were highly expressed during embryonic period. However, only 46.67% of the genes related to cerebellar atrophy were highly expressed during the embryonic period, with a larger proportion of genes being highly expressed after birth. This may be due to the fact that the cerebellum is one of the last brain structures to achieve maturity [59].

To investigate the expression profile of HSP genes during cortical development, we used the published database GSE38805 [60] and GSE65000 [61] to monitor the transcriptome expression profiles of SPG4/SPAST and SPG11/KIAA1840, which are the primary causes of AD HSP and AR HSP, respectively, across various regions of embryonic brain tissues in humans and mice. SPG11 showed higher expression in the ventricular zone (VZ) than in cortical plate (CP) in both the human and mouse cortex, whereas SPG4 showed higher expression in the CP compared with VZ. Consistently, SPG11 is highly enriched in the apical radial glial, whereas SPG4 is highly enriched in neurons (Figure 2B,C). These results suggest that the genes involved in AR HSP are more likely to be correlated with progenitor cells and early neurodevelopment.

4 HSP Proteins Play Roles in Brain Development

Brain development is a highly ordered process that is subject to precise temporal and spatial regulation. Neural stem cells possess self-renewal capabilities and multilineage differentiation potential. Under specific conditions, neural stem cells can differentiate into neurons, oligodendrocytes, and astrocytes [62]. Immature neurons migrate from their origin to specific sites where they are organized into layers, nuclei, and ganglia of neuronal cell bodies. Subsequently, these neurons sprout axons and dendrites, which can extend for several centimeters, to establish synaptic connections with target neurons or other cellular entities [63] (Figure 3).

5 Limitations

Most studies revealed the clinical manifestation of HSP patients with certain time period, it remained unclear whether brain abnormality such as atrophy of the brain or cerebellum is result from developmental or degenerative condition.

To distinguish between the role of neural development and degeneration, it is necessary to observe and study the entire life cycle of patients. Since most HSPs are reported with early (neonatal, infancy, or childhood) onset, HSP causing genes are more likely to play pivotal roles in growth and development [112]. However, there is still limited research on the developmental mechanisms of related genes. In addition, conventional knock out of some HSP genes such as Vps37a and Ubap1 result in embryonic lethal in mice, which limit the study of gene function on brain development.

6 Concluding and Prospects

The accepted dogma divides neurodegenerative and neurodevelopmental diseases apart. However, emerging evidence indicates that neurogenetic conditions associated primarily with neurodegeneration also affect neurodevelopment [113]. Here we summary the clinical manifestation, gene expression, and protein function of HSP. We found disruption of some HSP proteins led to global neurodevelopmental delay, microcephaly, and other developmental disorders (Figure 1). These phenotypes were supported by the fact that HSP genes play roles in the proliferation and differentiation of neural stem cells, as well as in the migration and maturation of neurons (Figure 3). In addition, the early expression pattern of some HSP genes in the human brain further supports their role in neural development (Figure 2). Most genes are expressed abundantly during critical developmental stages after conception. Due to the role of HSP genes in neural development, early identification and intervention may help mitigate disease progression and improve patients' quality of life. By analyzing the clinical manifestations and gene expression patterns of patients, possible subtypes of HSP can be inferred and targeted screening can be carried out. Consequently, this implies that we have the potential to assess the likelihood of neurodegenerative diseases via early developmental diagnosis, potentially even delaying the onset and progression of these diseases through timely intervention.

Neurodegenerative diseases are usually characterized by progressive neuronal loss and dysfunction, whereas neurodevelopmental diseases involve abnormalities in neuronal development. For example, cerebellar hypoplasia is a condition in which the cerebellum fails to reach its normal size during development, whereas cerebellar atrophy is a condition in which the cerebellum decreases in size due to neuronal loss. Both conditions reflect vulnerabilities in the development and maintenance of the nervous system. A typically biphasic disease course of late-onset neurodegeneration occurred on the background of a neurodevelopmental disorder [114]. The close connection with neurodegenerative disorders highlights the relevance of research into rare early-onset neurodevelopmental conditions for much more common, age-related human diseases. Although HSP has traditionally been recognized as a neurodegenerative disease, there is growing evidence that the pathogenesis of HSP involves abnormalities in neurodevelopment. The fact that most patients with HSP present with symptoms in infancy or even neonatally, emphasizes the importance of recognizing HSP as a “neurodevelopmental-related disorder”.

Since HSP is a neurogenetic disorder, mutation of proteins happens at the very beginning of organ development. Some HSP proteins have been proved to play import roles in different process of normal brain development. Neurogenesis is active during the embryonic period, as it is responsible for producing new neurons. The decreased proliferation of NPC results in a smaller population of neurons, potentially impacting the reserve available for replacing degenerated or diseased nerve cells in later stages, ultimately causing neurodegenerative symptoms. Neuronal migration, neurite outgrowth, and synaptic plasticity all contribute to maintain neural network connections. This abnormal development might be partly responsible for the selective vulnerability of neurons in degenerative diseases [113]. Finally, HSP proteins have been implicated in signaling pathways associated with neurodevelopment, such as Wnt and BMP signaling [65, 75]. Understanding the roles and signaling pathways of these proteins during development may -offer new drug targets for therapy and predictors of susceptibility useful for prevention of HSP.

HSPs can be diagnosed early through genetic screening, measures of growth, including height, weight, and body mass index, between child and adolescent carriers of HSP associated mutations and control peers will help to identify the developmental trajectory of HSPs. In addition, as the formation of the Sylvian fissure appears early in utero [115], various 3D reconstruction of sulcal features can then be analyzed to explore the genetic interplay with neurodevelopment. Ultimately, examining the roles of HSP genes using spatiotemporal specific genetic knockout mice and organoids derived from HSP patients is crucial for dissecting the consequences of deletion/mutation on early neural development.

Overall, as HSP is a phenotypically and genotypically diverse group of monogenic diseases, collaborative and multidisciplinary efforts are required to provide systemic insights into both the clinical manifestation and pathogenesis of HSP, which will benefit for developing effective therapeutic strategies.

Author Contributions

Manuscript conception and design: D.X. and Y.Z.; literature search and data analysis: D.X., Y.Z., Y.S., and D.L.; manuscript writing: Y.Z. and D.X. All authors approved the final version of this manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.