A genetic model for Endosomal Microautophagy

Aging-associated diseases are an increasing socio-economic burden despite efforts to improve healthspan. Pathologies that cause degeneration of the nervous system are particularly devastating, and in many cases are associated with decline in proteostasis and lysosomal malfunction. Prime examples are Parkinson and Alzheimer’s disease that are characterized by accumulation of insoluble protein aggregates that lead to neuronal decay. Autophagy delivers cytosolic components to lysosomes for degradation and is thus essential for cellular homeostasis and to cope with different stressors. Macroautophagy (MA) can selectively degrade organelles or aggregated proteins, but selective degradation of single proteins has only been described for Chaperone-mediated autophagy (CMA) and endosomal Microautophagy (eMI). These two autophagic pathways, described to date only in mammals, are specific for proteins containing KFERQ-related targeting motifs. In collaboration with the Cuervo lab, we have established a genetic model for eMI inDrosophila in vivo. We are thus for the first time able to perform genetic screens for regulatory components of eMI, this only recently identified form of autophagy about which barely anything is known. 

Lysosomes are also important regulatory hubs that integrate nutritional signals and participate in lipid metabolism. We have recently characterized Drosophila Lamp1, a bona fide homolog of the mammalian LAMP1/2. Lamp1 deficiency results in an increase in the number of acidic organelles in the fat body, strongly suggesting defects in the regulation of the pH of the endolysosomal system. Furthermore, Lamp1 mutant larvae have elevated levels of sterols and diacylglycerols, indicating functions of Lamp1 in lipid transport beyond sterols. Significantly, these phenotypes are similar to loss of glucocerebrosidase, the gene causing Gaucher disease and a major risk factor for Parkinson.

Rho kinase and its effector Cmb in spermiogenesis

During development, genetic and molecular programs control the differentiation of various cell types and orchestrate their morphogenetic behaviors to form organs with specific functions. Organogenesis requires the coordination of cell polarity, cellular movement, and cell shape, driven by intercellular signaling and the tissue-specific interpretations of these signals. Traditionally, Rho kinase (Rok) functions as effector of the non-canonical Wnt/Frizzled PCP pathway during gastrulation and neural tube formation. In a systematic, genome-wide screen, we have identified the previously uncharacterized Combover, an intrinsically disordered protein as novel Rok substrate. Significantly, our follow up studies have identified a novel and unanticipated role of Rok and Cmb during spermiogenesis. We currently address how, downstream of Rok, Combover orchestrates the transition between axoneme elongation and sperm individualization by coordinating the actin and microtubule cytoskeletons with the plasma membrane, thus ensuring proper resolution of the syncytial spermatids into functional sperm that are encapsulated by their own plasma membrane. The biomedical significance of sperm individualization is further exemplified by the presence of multiciliate spermatozoa and spermatids with unresorbed cytoplasm in infertile men.

It is our goal to use Drosophila as model system to address fundamental questions that are relevant for development and disease in general. 

Reviews and commentaries

Handy, J., MacIntosh, G.C.*, Jenny, A.* (2023) Ups and downs of lysosomal pH: conflicting roles of LAMP proteins? Autophagy,doi:10.1080/15548627.2023.2274253

Herpin, A., Lescat, L., Bobe, J., Jenny, A., Seiliez, I. (2020) Lighting Chaperone-Mediated Autophagy (CMA) evolution with an ancient LAMP: the existence of a functional CMA activity in fish. Autophagy, DOI: 10.1080/15548627.2020.1797344

Rodan, A.R.*, Jenny, A.* (2017) WNK kinases in development and disease. Edited by Jenny, A. Curr. Top. Dev. Bio. 123:1-47

Baker, N.E. **, Jenny, A.** (2014) Metabolism and the other fat: a protocadherin in mitochondria (Preview). Cell 158, 1240-1. PMID: 25215484.

Serysheva^, E., Mlodzik^, M*., Jenny, A*. (2014). WNKs: An Unexpected Role in Wnt/b-catenin Signaling. Invited Feature Article, Cell Cycle 13(2) 173-174.

Maung, S. M. T., Jenny, A. (2011). Planar Cell Polarity in Drosophila. Edited by Carroll, T. Organogenesis, Organogenesis 7(3) 165-179.

Jenny, A. Planar Cell Polarity in the Drosophila Eye. Edited by Reh, T. and Cagan, R. (2010). Curr. Top. Dev. Bio. 93, 189-227.

Primary Articles (selection)

Dutta, D., Kanca, O., Shridharan, R., Marcogliese, P., Steger, B., Morimoto, M., Frost, G., Macnamara, E., Undiagnosed Diseases Network, Wangler, M., Yamamoto, S., Jenny. A., Adams, D., C. Malicdan, M., Bellen, H. (2024) Loss of the endoplasmic reticulum protein TMEM208 affects cell polarity and multicellular development. PNAS e2322582121.

Yarikipati, P., Jonusaite, S., Pleinis, J. M., Dominicci Cotto, C., Sanchez-Hernandez, D., Morrison, D. E., Goyal, S., Schellinger, J., Penalva, C., Curtiss, J., Rodan*, A. R., Jenny, A.*  (2023) Unanticipated domain requirements for Drosophila Wnk kinase in vivo. PLoS Genet 19, e1010975.

Rahmani, Z.*, Surabhi, S., Rojo-Cortés, F., Dulac, A., Jenny, A.*, Birman, S.* (2022) Lamp1 Deficiency Enhances Sensitivity to α-Synuclein and Oxidative Stress in Drosophila Models of Parkinson Disease. Int J Mol Sci, DOI: 10.3390/ijms232113078.

Chaudhry, N.*, Sica, M.*, Surabhi, S.*, Sanchez Hernandez, D., Mesquita, A., Selimovic, A., Riaz, A. Lescat, L., Bai, H., Macintosh, G, C.*, Jenny, A*. (2022) Lamp1 mediates lipid transport, but is dispensable for autophagy in Drosophila. Autophagy doi: 10.1080/15548627.2022.2038999

Mesquita, A., Glenn, J., Jenny, A. (2020) Differential activation of eMI by distinct forms of cellular stress. Autophagy, doi: 10.1080/15548627.2020.1783833.

Mesquita, A., Pereira, J., Jenny, A.* (2019) Streamlined Particle Quantification (SParQ) plugin is an automated fluorescent vesicle quantification plugin for particle quantification in Fiji/ImageJ. Autophagy, doi: 10.1080/15548627.2019.1695400.

Domingos P. M., Jenny A, Combie, K.F., Del Alamo, D., Mlodzik M., Steller, H., Mollereau, B. (2019) Regulation of Numb during planar cell polarity establishment in the Drosophila eye. Mech Dev, doi: 10.1016/j.mod.2019.103583.

Steinhauer, J.*, Statman, B, Fagan, J., Borck, J., Surabhi, S., Yarikipati, P., Edelman, D., Jenny, A.*(2019) Combover interacts with the axonemal component Rsp3 and is required for sperm individualization. Development, 146(17). pii: dev179275. doi: 10.1242/dev.179275

Issa. A.R., Sun, J., Petitgas, C., Mesquita, A., Jenny, A., Chérif-Zahar, B., Birman, S. (2018). The human receptor for chaperone-mediated autophagy LAMP-2A protects Drosophila against starvation, oxidative stress, and α-synuclein pathogenicity, Autophagy, doi: 10.1080/15548627.2018.1491489. 35.

Collu, G.M., Jenny, A., Gaengel, K., Mirkovic, I., Chin, M.L., Weber, U., Smith, M.J., Mlodzik, M. Prickle is phosphorylated by Nemo and degraded to maintain Prickle/Spiny-legs isoform balance during planar cell polarity establishment. PLoS Genetics, 14(5): e1007391. doi: 10.1371/journal.pgen.1007391.

Kaur, P., Yuk Man Lam, V., Mannava, A., Suresh, J., Jenny, A., Tolwinski, N. (2017). Membrane Targeting of Disheveled Can Bypass the Need for Arrow/LRP5. Sci. Rep., in press.

Jahanshahi, M., Hsiao, K., Jenny, A., Pfleger, C. M. (2016) The Hippo Pathway targets the Cdh1/fzr inhibitor Rae1 to regulate mitosis and establish organ size. PLoS Genetics 12(8):e1006198. doi: 10.1371/journal.pgen.1006198.

Mukherjee, A., Patel, B., Koga, H., Cuervo, AM., Jenny, A. (2016). Selective endosomal microautophagy is starvation inducible in Drosophila. Autophagy 12 (11), 1984-1999.

Dollar, G., Barnett, A.A., Gombos, R., Sanchez Hernandez, D., Maung, S.M.T, Mihály, Jenny, A. (2016). Unique and overlapping functions of formins Frl and DAAM during PCP signaling and neuronal development in Drosophila. Genetics 202 (3), 1135-1151.

Gombos, R., Migh, E., Antal, O., Mukherjee, A., Jenny, A., Mihály, J. (2015)The Formin DAAM Functions as Molecular Effector of the Planar Cell Polarity Pathway during Axonal Development in Drosophila. J. Neuroscience, 35 (28),10154-67.

Fagan, J.K., Dollar, G., Lu, Q., Barnett, A., Pechuan Jorge, J., Schlosser, A., Pfleger, C., Adler, P., Jenny, A..* (2014) Combover/ CG10732, a novel PCP effector for Drosophila wing hair formation. PLoS One,9(9):e107311. doi: 10.1371. PMID: 25207969.

*co-first authors or co-corresponding authors