Stard6, a member of the StAR-related lipid transfer (START) domain family of proteins, has functions related to intracellular cholesterol transport. Proteins in this family play roles in non-vesicular lipid and sterol transport, and Stard6 may contribute to steroidogenesis, an important pathway in the body [2,3,7].

In the human ovary, Stard6 mRNA was identified, but the primary transcript was a splice variant and no protein was detected. Cyclic AMP analog and phorbol ester, which affect steroidogenesis-related pathways, did not impact Stard6 transcripts, suggesting it may not have a direct role in supplying cholesterol for ovarian steroidogenesis [1]. In porcine ovarian cells, Stard6 mRNA and protein were present, with the highest levels in mid-luteal phase corpus luteum. Transfection experiments in non-steroidogenic COS-1 cells showed that Stard6 could enhance pregnenolone production, indicating its potential role in ovarian steroidogenesis [2].

In the nervous system, studies found that the morphological characteristics of Stard6 were different from those of StAR. Also, Stard6 immunoreactivity changed with DNA-dependent protein kinase, and its distribution in the hippocampus was different from StAR, both in normal and epileptic conditions [4].

In addition, in Alzheimer's disease, the rs10164112-T allele of STARD6, when combined with the APOE ε4 allele, was a risk factor in the Han Chinese population, and in elderly APOE ε4 carriers, the TT genotype of rs10164112 might be a protective factor against mild cognitive impairment [5,6].

In summary, Stard6 has potential functions in steroidogenesis, especially in ovarian cells. Its role in the nervous system is distinct from StAR. In the context of neurodegenerative diseases like Alzheimer's disease and mild cognitive impairment, certain STARD6 polymorphisms in combination with the APOE ε4 allele are associated with disease risk or protection. Studies on Stard6 using genetic models can further clarify its functions in these biological processes and disease conditions.

References:

1. Yahya, Nawal A, King, Steven R, Shi, Bo, Whitman-Elia, Gail F, LaVoie, Holly A. 2024. Differential regulation of STARD1, STARD4 and STARD6 in the human ovary. In The Journal of endocrinology, 262, . doi:10.1530/JOE-23-0385. https://pubmed.ncbi.nlm.nih.gov/38829257/

2. LaVoie, Holly A, Whitfield, Nicole E, Shi, Bo, Bose, Himangshu S, Hui, Yvonne Y. 2014. STARD6 is expressed in steroidogenic cells of the ovary and can enhance de novo steroidogenesis. In Experimental biology and medicine (Maywood, N.J.), 239, 430-5. doi:10.1177/1535370213517616. https://pubmed.ncbi.nlm.nih.gov/24595982/

3. Létourneau, Danny, Bédard, Mikaël, Cabana, Jérôme, LeHoux, Jean-Guy, Lavigne, Pierre. 2016. STARD6 on steroids: solution structure, multiple timescale backbone dynamics and ligand binding mechanism. In Scientific reports, 6, 28486. doi:10.1038/srep28486. https://pubmed.ncbi.nlm.nih.gov/27340016/

4. Chang, In Youb, Jeon, Young Jin, Jung, Sung Mi, Park, Kyung Soo, Yoon, Sang Pil. 2010. Does the StarD6 mark the same as the StAR in the nervous system? In Journal of chemical neuroanatomy, 40, 239-42. doi:10.1016/j.jchemneu.2010.06.006. https://pubmed.ncbi.nlm.nih.gov/20609383/

5. Yin, Jiajun, Feng, Wei, Yuan, Hongwei, Jin, Chunhui, Cheng, Zaohuo. 2019. Association analysis of polymorphisms in STARD6 and near ECHDC3 in Alzheimer's disease patients carrying the APOE ε4 Allele. In Neuropsychiatric disease and treatment, 15, 213-218. doi:10.2147/NDT.S186705. https://pubmed.ncbi.nlm.nih.gov/30666118/

6. Wu, Yue, Yin, Jiajun, Yang, Bixiu, Zhao, Xingfu, Cheng, Zaohuo. 2021. Association Analysis of Polymorphisms in BIN1, MC1R, STARD6 and PVRL2 with Mild Cognitive Impairment in Elderly Carrying APOE ε4 Allele. In Neuropsychiatric disease and treatment, 17, 1125-1133. doi:10.2147/NDT.S296144. https://pubmed.ncbi.nlm.nih.gov/33907405/

7. Bose, Himangshu S, Whittal, Randy M, Ran, Yong, Baker, Bo Y, Miller, Walter L. 2008. StAR-like activity and molten globule behavior of StARD6, a male germ-line protein. In Biochemistry, 47, 2277-88. doi:10.1021/bi701966a. https://pubmed.ncbi.nlm.nih.gov/18211099/