ALDH1A2

Aldehyde dehydrogenase 1 family, member A2, also known as ALDH1A2 or retinaldehyde dehydrogenase 2 (RALDH2), is an enzyme that in humans is encoded by the ALDH1A2 gene.

This protein belongs to the aldehyde dehydrogenase family of proteins. The product of this gene is an enzyme that catalyzes the synthesis of retinoic acid (RA) from retinaldehyde. Retinoic acid, the active derivative of vitamin A (retinol), is a paracrine hormone signaling molecule that functions in developing and adult tissues. The studies of a similar mouse gene suggest that this enzyme and the cytochrome CYP26A1, concurrently establish local embryonic retinoic acid levels that facilitate posterior organ development and prevent spina bifida. Three transcript variants encoding distinct isoforms have been identified for this gene.

Involvement in T-ALL
Cancer can be caused by both internal factors including genetic changes or environmental/acquired factors. Many forms of cancers have overexpressed aldehyde dehydrogenase (ALDH), specifically one of the ALDH family genes, ALDH1A2 which has been abnormally expressed in more than half of instances of T-cell acute lymphoblastic leukemia (T-ALL). Its molecular nature and contribution to the pathophysiology of T-ALL remain largely not well understood. T-ALL is an acute leukemia that arises from immature T-cell precursors and is an aggressive form of cancer that primarily affects children but can also be found in adults. T-ALL has multiple genes encoding transcription factors including TAL1, TLX1, HOXA genes, TAL2, LYL1, LMO1, LMO2, and NKX3 though ALDH1A2 is one of the recognized downstream targets of TAL1. which works by binding to the intronic regulatory element of the gene thereby inducing T-ALL specific isoform with enzymatic activity. TAL-1 positive T-ALL accounts for approximately 40-60% of all primary cases. According to researchers’ data, depletion of ALDH1A2 demonstrated reduced cell viability in T-cell lines and caused apoptosis. ALDH1A2 has a role in glycolysis and the TCA during which it affects multiple metabolic enzymes to promote ATP production though depletion of ALDH1A2 revealed increased levels of reactive oxygen species. However, overexpression of ALDH1A2 findings suggested that it can increase tumor onset and tumor penetrance. Overall, it has been noted per researchers' data and  findings that the ALDH1A2 can promote T-ALL cell metabolism due to direct activation by TAL-1 and promote leukemia cell survival and protect against intracellular stress by reducing the level of reactive oxygen species.

Potential suppressor in prostate cancer
Due to ADLDH1A2's involvement in the conversion of retinal to RA, researchers have keen on understanding its role in different pathologies. RA has pro-differentiation properties including promoting apoptosis, differential, and cell growth arrest. It was observed that the ALDH1A2 can be expressed in epithelia from normal prostate though not from prostate cancer. Upon bisulfite sequencing, it was found that the ALDH1A2 promoter region was hypermethylated in primary prostate tumors compared with normal prostate specimens after DU145 cells which express retinoid receptors were cultured in the presence of either ATRA or 5-aza-DC. 5-Aza-DC can induce expression of ALDH1A2. Findings suggested that ALDH1A2 is a candidate tumor suppressor in prostate cancer and this provided further evidence of retinoids in the treatment or prevention of prostate cancer.

Congenital heart disease
ALDH1A1 is also a key step in cardiac development due to its involvement in the RA signaling pathway. RA regulates various cellular behaviors during early development and adult homeostasis. In particular, the vertebrate heart is affected by variations in RA signaling which can produce cardiac and vascular malformation. It is vital to note that RA cannot be synthesized de novo due it being a carotenoid and thus it must be acquired by preformed animal-derived precursors such as retinol or retinyl esters. One of the metabolic routes used to produce RA in humans is by synthesizing retinol after it has been oxidized to retinaldehyde then to RA through various enzymes including alcohol dehydrogenases and aldehyde dehydrogenases. The second step is an irreversible conversion from retinaldehyde to RA which is converted by ALDH1A2. A study was conducted by researchers on the screening of patients with congenital heart diseases for genetic variation at the ALDH1A2 locus through bi-directional sequencing. Congenital heart disease (CHD)  was initially thought to be multifactorial and polygenic disease; however, recent literature of familial forms of CHD such as hypertrophic cardiomyopathy, atrial septal defect, ventricular septal defect, and tetralogy of fallot are being explained by haploinsufficiency of genes including sarcomeric proteins, extracellular matrix proteins, transcription factors, and ionic channels. Through this study's methods and research, it was found that ALDH1A2 genetic variation is present in tetralogy of fallot patients meaning that it can play a potential role in human cases of CHD; however, there is no clear link on whether the variation at the ALDH1A2 locus is a significant modified of the risk for CHD.

Glioblastoma
In the ALDH1 family of genes, ALDH1A2 is one of the most familiar enzymes represented in human tissue alongside ALDH1A1 and ALDH1A3; however each have differing tissue distributions but still catalyze the synthesis of RA. RA has also been employed as a therapeutic agent in the treatment of glioblastoma (GBM) though with limitations. Glioblastoma is an aggressive and malignant brain tumor and due to its heterogeneity, it is more difficult to treat. In another study published in 2021, the expression of ALDH1A2 in the GBM microenvironment was conducted. The study's results demonstrated that the M2 glioblastoma associated macrophages (GBM) highly express ALDH1A2 when compared to other ALDH family proteins and that the higher expression was increased with tumor recurrence at the gene and protein levels. The effect of ALDH1A2 and the effect RA on GBM tumor cells still requires further understanding and knowledge though researchers were able to gather that ALDH1A2 may promote a progressive phenotype of GBM.

Potential treatment of osteoarthritis
In addition, ALDH1A2, which is a key enzyme for synthesis of all-trans retinoic acid (atRA) that is associated with severe hand osteoarthritis. Osteoarthritis (OA) is a degenerative joint disease which can have symptoms including weakness, stiffness in joints, and limited range that can significantly impact many individuals as they age though conventional disease-modifying treatments are not used for treatment. OA treatment is primarily focused on decreasing joint stress through exercise, pain medications, and using assistive devices such as canes. Zhu and her colleagues further explored in a research study how the variants in the ALDH1A2 gene which synthesizes atRA can be used with those with severe hand OA. The relationship between ALDH1A2 mRNA and inflammatory genes was viewed that revealed a reciprocal relationship. Many believe that the primary perpetuating factor of OA is from mechanoflammation which the research study describes as “articular cartilage injury that becomes upregulated by similar inflammatory genes.”   The study used a retinoic acid metabolism blocking agent (RAMBA) called talarozole which works by reducing inflammation and cartilage injury by a peroxisome proliferator activated receptor gamma and the results demonstrated that RAMBAs may be a potential therapeutic option for the treatment of OA as a disease modifying drug by suppressing mechanoflammation in the articular cartilage.