CAD (Carbamoyl-phosphate synthetase 2, Aspartate transcarbamoylase, and Dihydroorotase) is a multifunctional protein that participates in the initial three speed-limiting steps of pyrimidine nucleotide synthesis. Over the past two decades, extensive investigations have been conducted to unmask CAD as a central player for the synthesis of nucleic acids, active intermediates, and cell membranes. Meanwhile, the important role of CAD in various physiopathological processes has also been emphasized. Deregulation of CAD-related pathways or CAD mutations cause cancer, neurological disorders, and inherited metabolic diseases. Here, we review the structure, function, and regulation of CAD in mammalian physiology as well as human diseases, and provide insights into the potential to target CAD in future clinical applications.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders that manifest various motor and nonmotor symptoms. Although currently available therapies can alleviate some of the symptoms, the disease continues to progress, leading eventually to severe motor and cognitive decline and reduced life expectancy. The past two decades have witnessed rapid progress in our understanding of the molecular and genetic pathogenesis of the disease, paving the way for the development of new therapeutic approaches to arrest or delay the neurodegenerative process. As a result of these advances, biomarker‐driven subtyping is making it possible to stratify PD patients into more homogeneous subgroups that may better respond to potential genetic‐molecular pathway targeted disease‐modifying therapies. Therapeutic nucleic acid oligomers can bind to target gene sequences with very high specificity in a base‐pairing manner and precisely modulate downstream molecular events. Recently, nucleic acid therapeutics have proven effective in the treatment of a number of severe neurological and neuromuscular disorders, drawing increasing attention to the possibility of developing novel molecular therapies for PD. In this review, we update the molecular pathogenesis of PD and discuss progress in the use of antisense oligonucleotides, small interfering RNAs, short hairpin RNAs, aptamers, and microRNA‐based therapeutics to target critical elements in the pathogenesis of PD that could have the potential to modify disease progression. In addition, recent advances in the delivery of nucleic acid compounds across the blood–brain barrier and challenges facing PD clinical trials are also reviewed.

Rare diseases affect almost 500 million people globally, predominantly impacting children and often leading to significantly impaired quality of life and high treatment costs. While significant contributions have been made to develop effective treatments for those with rare diseases, more rapid drug discovery strategies are needed. Therapeutic antisense oligonucleotides can modulate target gene expression with high specificity through various mechanisms determined by base sequences and chemical modifications; and have shown efficacy in clinical trials for a few rare neurological conditions. Therefore, this review will focus on the applications of antisense oligonucleotides, in particular splice-switching antisense oligomers as promising therapeutics for rare neurological diseases, with key examples of Duchenne muscular dystrophy and spinal muscular atrophy. Challenges and future perspectives in developing antisense therapeutics for rare conditions including target discovery, antisense chemical modifications, animal models for therapeutic validations, and clinical trial designs will also be briefly discussed.

Polyglutamine (polyQ) ataxias are a heterogenous group of neurological disorders all caused by an expanded CAG trinucleotide repeat located in the coding region of each unique causative gene. To date, polyQ ataxias encompass six disorders: spinocerebellar ataxia types 1, 2, 3, 6, 7, and 17 and account for a larger group of disorders simply known as polyglutamine disorders, which also includes Huntington’s disease. These diseases are typically characterised by progressive ataxia, speech and swallowing difficulties, lack of coordination and gait, and are unfortunately fatal in nature, with the exception of SCA6. All the polyQ spinocerebellar ataxias have a hallmark feature of neuronal aggregations and share many common pathogenic mechanisms, such as mitochondrial dysfunction, impaired proteasomal function, and autophagy impairment. Currently, therapeutic options are limited, with no available treatments that slow or halt disease progression. Here, we discuss the common molecular and clinical presentations of polyQ spinocerebellar ataxias. We will also discuss the promising antisense oligonucleotide therapeutics being developed as treatments for these devastating diseases. With recent advancements and therapeutic approvals of various antisense therapies, it is envisioned that some of the studies reviewed may progress into clinical trials and beyond.

Promising therapeutic strategies are being explored to replace or regenerate the neuronal populations that are lost in patients with neurodegenerative disorders. Several research groups have attempted direct reprogramming of astrocytes into neurons by manipulating the expression of polypyrimidine tract-binding protein 1 (PTBP1) and claimed putative converted neurons to be functional, which led to improved disease outcomes in animal models of several neurodegenerative disorders. However, a few other studies reported data that contradict these claims, raising doubt about whether PTBP1 suppression truly reprograms astrocytes into neurons and the therapeutic potential of this approach. This review discusses recent advances in regenerative therapeutics including stem cell transplantations for central nervous system disorders, with a particular focus on Parkinson’s and Alzheimer’s diseases. We also provide a perspective on this controversy by considering that astrocyte heterogeneity may be the key to understanding the discrepancy in published studies, and that certain subpopulations of these glial cells may be more readily converted into neurons.

Parkin-type autosomal recessive juvenile-onset Parkinson’s disease is caused by mutations in the PRKN gene and accounts for 50% of all autosomal recessive Parkinsonism cases. Parkin is a neuroprotective protein that has dual functions as an E3 ligase in the ubiquitin–proteasome system and as a transcriptional repressor of p53. While genomic deletions of PRKN exon 3 disrupt the mRNA reading frame and result in the loss of functional parkin protein, deletions of both exon 3 and 4 maintain the reading frame and are associated with a later onset, milder disease progression, indicating this particular isoform retains some function. Here, we describe in vitro evaluation of antisense oligomers that restore functional parkin expression in cells derived from a Parkinson’s patient carrying a heterozygous PRKN exon 3 deletion, by inducing exon 4 skipping to correct the reading frame. We show that the induced PRKN transcript is translated into a shorter but semi-functional parkin isoform able to be recruited to depolarised mitochondria, and also transcriptionally represses p53 expression. These results support the potential use of antisense oligomers as a disease-modifying treatment for selected pathogenic PRKN mutations.