In Parkinson's disease, it suggests that lipids can accumulate within cells through degradation of lysosomal function. Variant of possess1 Genes, the most powerful genetic risk factor for sporadic PD, are partially responsible. possess1 It encodes glucocerebrosidase enzymes that are useful in lipid processing. but possess1 Variants alone do not fully explain the reduction in GCASE activity in PD. Currently, scientists led by Dimitri Krein of Northwestern University Feinberg School of Medicine in Chicago, report that another family of genes may be involved. Science on April 11th describes the link between GCASE activity and the commander complex. This helps endosomal cargo recycle plasma cargo into plasma membranes.

  • GBA1 mutations alone do not explain lysosomal dysfunction in PD.
  • Loss of endosomal recycled proteins renders this lysosomal enzyme crippled.
  • Without the protein called CommD3, cells will exhale that they will become lysosomes in exosomes.

“Our data has discovered new features of this complex,” Krainc told Alzforum. Previously, he and his collaborators explained how GCASE dysfunction leads to accumulation of α-synuclein in PD neurons and vice versa. This helped explain the relationship between PD and Gaucher's illness. possess1 Mutations (see Mazzulli et al. , 2011).

The pathways determining the outcomes of these different diseases are still unclear, noting David Sulzer of Columbia University Medical Center, New York, who was not involved in either study. “This is a great study that has identified ways to differentially process lysosomal cargo. This approach has enabled the identification of many different proteins that regulate lysosome organelles, allowing researchers to focus on the specific pathways that regulate many human trafficking steps and components.

To identify other genes possess1 It affected lysosomal GCASE activity, and the first author, Georgia Minakaki and colleagues performed a genome-wide CRISPR interference screen. This revealed 338 genes that could affect lysosomal GCASE function. Of the 190 genes that have reduced activity, the top hit is the mouthful of “three containing copper metabolism MURR1 domains.” CommD3 and other members of the CommD family combine with human trafficking proteins called CCDC22 and CCDC93 to form a 12 protein complex called CCC. This is one component of the Commander Complex. Others were retrievers, washes, and dennd10, all of which participated in endosomal recycling independently of the retromer complex.

The author discovered that knockout comd3 Lysosomal GCASE activity in human embryonic kidney cells was reduced by halving and attenuating lysosomal GCases of microglia and neurons derived from human IPSCs. It also infringed the CCC complex and ruled out CCDC22. Adding commd3 to these cells rescued commd1 formation and CCDC2 expression, as well as GCase activity.

Endolysosome isolation revealed a significant difference in lysosomal protein levels between CommD3 knockout and wild-type cells. The researchers measured almost 40% less measurements of LAMP2, LIMP-2, GCASE, and cathepsin B in lysosomes in knockout cells. These cells also do not do much effective prosposin and progranulin. Progranlin treatment helps maintain lysosomal function, while prosposin helps these organelles metabolize lipids (see Simon et al. , 2022; Meyer et al. , 2014).

Encapsulated endosomes. After leaving Golgi (Turquoise Dot) 0-15 minutes Column), Gcase (yellow) and Limp2 (Magenta)co–Localize with endosomes (turquoise in rows for 60-120 min) of Comm3 knockout (lower row) but not in wild-type HEK cells (upper row). [Courtesy of Minakaki et al., Science, 2025.]

Both the CCC and commander complexes are involved in endosome recycling, so researchers wondered whether it would help direct lysosomal proteins to their destinations. They tracked Limp-2 and Gcase in HEK cells. In CommD3 knockout, these proteins were captured by post-Golgi vesicles, some of which appeared to be early endosomes (image above). Examining extracellular vesicles from wild-type and knockout cells, Minakaki discovered more of the latter lysosomal proteins LAMP1, LIMP-2, and HEXB. Similarly, extracellular vesicles of iPSC-derived neurons lacking COMMD3 contained 12 times more LAMP1 and 3 times more HEXB than extracellular vesicles of wild-type neurons. The authors stated that they interpret the findings to suggest that the CCC-command complex affects the fate of lysosomal proteins.

To further investigate, the authors searched genomics data for links between PD and protein variants of these complexes. In the UK, we found that combinations of CCC family, CCC complex, or commander complexes are common in at least twice as many controls as PD in the biobank full-text cohort and whole-genome AMP-PD cohort (6,166 PD cases and 109,467 controls). One individual gene with a significant effect was CommD9however, only in the UK biobank cohort.

The authors acknowledge that loss-of-function variants of these complexes can be extremely rare, as hundreds of plasma membrane proteins need to be exchanged. The larger the sample size, the more likely it is to discover links between individual commander complex proteins and PD, DLB, and other neurodegenerative diseases, they write.

Lauren Schneider is a freelance writer in New York City.

Paper quote

  1. Jr, Xu YH, Sun Y, Sun AL, McLean PJ, Caldwell GA, Cydansky E, Grabbowski GA, Krainc D.
    Gaucher's disease glucocerebrosidase and α-synuclein form bidirectional pathogenic loops in syncreinopathy.
    cell. July 8, 2011; 146(1): 37-52. Pack 2011 13
    PubMed.
  2. Simon MJ, Logan T, DeVos SL, Paolo g.
    Lysosomal function of progranlin and its impact on the treatment of frontotemporal dementia.
    Trends Cell Biol. October 13, 2022;
    PubMed.
  3. Meyer RC, Giddens MM, Coleman BM, Hall RA.
    Protective roles of prosaposin and its receptors in the nervous system..
    Brain resolution. October 17, 2014 October 1585: 1-12. EPUB 2014 August 15th
    PubMed.