The meeting entitled “Common mechanisms in childhood and adult neurodegenerative disorders” was hosted together with the German Center for Neurodegenerative Diseases (DZNE).  It took place at the DZNE in Bonn in June.

A brief welcome, introduction and thanks to the sponsors was given by Sabina Tahirovic (DZNE) and Frank Stehr (NCL-Stiftung). Frank also announced the 2nd Neurodegeneration Research Award given by the NCL-Stiftung (100.000 EUR prize money, more details you will find in this Newsletter). Scientists can now apply for this award. Back to the meeting itself, a number of leading scientists working on childhood and/or adult onset neurodegeneration (ND) discussed common underlying themes and mechanisms including neuroinflammation, the role of microglia, mechanisms driving endo-lysosomal dysfunction, and lipid dyshomeostasis.

Angela Schulz (UKE, Hamburg) provided a clinical overview of CLN3 disease, the most common and juvenile form of NCL. She discussed phenotype variability in CLN3 patients, how this complicates efficacy readouts in clinical trials, and presented ways forward how to better manage these issues in future trials.

Susan Cotman (MGH, Boston, US) presented a detailed description of defects observed in microglia of the CLN37/8 mouse model, and in human CLN3 iPSC-derived microglia. She compared these defects to those seen in other NDs including Niemann-Pick type C (NPC) and Alzheimer`s Disease (AD). The work Susan presented was a collaborative effort with Sabina Tahirovic (DZNE, Munich), and for which they received the 1st Neurodegeneration Research Award in 2018. In brief, CLN3 microglia take up but cannot efficiently degrade myelin debris, show reduced lipid droplet formation, and increased cholesterol storage. The results have recently been published online in a preprint in bioRxiv.

Monther Abu-Remaileh (Stanford, US) discussed several new discoveries from his laboratory highlighting the crucial role of intra-lysosomal lipid metabolism in ND. In 2022 his lab published the breakthrough finding that CLN3-deficiency leads to a massive accumulation of glycerophosphodiesters (GPDs), as well as their immediate precursors, lyso-glycerophospholipids (LPGs), in the lysosome. GPDs are the ultimate end products of glycerophospholipid catabolism inside this organelle and CLN3 is required for their clearance. In 2023, another milestone paper was published showing that CLN5 encodes the lysosomal enzyme that makes the endo-lysosome-specific lipid bis(monoacylglycero)phosphate, BMP. BMP decorates the surface of intra-lysosomal vesicles and is crucial for the activity of a number of lipases and their cofactors. Its discovery, complex role, and many still outstanding questions were recently described and discussed in a review by Medoh & Abu-Remaileh, 2024. In another recent paper the lab showed that GPDs inhibit lysosomal phospholipid catabolism in CLN3 disease and that PLA2G15 and PLBD2 are major lysosomal phospholipases with phospholipase B activity. Monther next discussed their very recent findings showing that BMP, long thought to be a very stable lipid inside the lysosome, is in fact catabolized inside the lysosome by the lysosomal lipase PLA2G15. Several  neurodegenerative diseases including GRN-FTD, CLN3, CLN5, and NPC1 show abnormal BMP homeostasis and others have shown earlier that supplementing GRN-deficient cells or NPC cells with BMP restores storage phenotypes including gangliosidoses (GRN) and cholesterol storage (NPC).
In their recent paper, Monther, in collaboration with a group at Scenic Biotech in The Netherlands, describe a remarkable effect on prolonging survival of an NPC1 mouse model by knocking out PLA2G15. Altogether, these findings underline a key role of BMP homeostasis in NDs and might pave a way for treating a variety of NDs in the future.
Anja Capell (LMU, Munich) presented an overview of frontotemporal dementias (FTLDs) and the main known links to genes including those encoding Progranulin (PGRN), TAU, FUS, and TDP-43. Loss-of function mutations in the GRN gene are a major cause of FTDL with TDP-43 positive inclusions. To better understand the latter link, she showed that PGRN slows the maturation and limits the proteolytic activity of the lysosomal protease legumain (LGMN) and that LGMN activity is strongly elevated in the absence of GRN in mice and human iPSC-derived KO microglia, and when GRN levels are reduced as in FTLD-GRN patients’ brain. LGMN is secreted by microglia and internalized by neurons where LGMN causes pathological processing of TDP-43. As described in a recent online preprint, she provided substantial support for the hypothesis that LGMN is a key link between PGRN insufficiency and TDP-43 pathology, and for LGMN as a therapeutic target.
Sabina Tahirovic (DZNE, Munich) gave an overview of studies in her lab addressing the contribution of microglia in NPC1 disease. After summarizing earlier and mostly published data showing that loss of NPC1 enhances phagocytic uptake but impairs lipid trafficking in microglia she moved on to discuss recent findings in microglia-specific NPC1 knockout mice. These were generated to specifically address the role of NPC1-deficient microglia in an otherwise wildtype cellular brain environment. These data will hopefully be published soon.

Maria Loannou (University of Alberta, CAN) presented studies from her lab addressing the role of neuron to glia transport in Alzheimer`s disease.  Earlier, she had shown that Fatty Acid (FA) metabolism is coupled in neurons and astrocytes to protect neurons from FA toxicity during periods of enhanced activity. Her lab demonstrated that toxic FAs produced in hyperactive neurons are transferred to astrocytic lipid droplets by ApoE-positive lipid particles. She went on and showed that during oxidative stress, peroxidated lipids and iron are released from neurons by autolysosomal exocytosis. Failure to release these lipid-protein particles causes lipid hydroperoxide and iron accumulation and sensitizes neurons to ferroptosis (see here). She then showed newer findings that address specifically the role of ApoE2, E3, and E4 in neuron to glia lipid transport, and how this could bear on developing new therapeutics. These findings will hopefully be published in the near future.
Rik van der Kant (VU, Amsterdam) presented the Neurolipid Atlas, that just went online. This is a lipidomics resource of iPSC-derived brain cells including neurons, microglia, and astrocytes derived from an iPSC stem cell line that is used for large-scale collaborative studies. These studies uncovered cholesterol as a regulator of astrocyte activation impaired by ApoE4. He also discussed how screening for drugs that can restore lipidomics phenotypes might pave the road to new therapies.

Christian Behrends (LMU, Munich) discussed findings exploring the role of TECPR2 in ND. Mutations in the gene encoding for Tectonin β-propeller repeat containing protein 2 (TECPR2) cause hereditary sensory and autonomic neuropathy (HSAN9). TECPR2 is required for lysosomal consumption of autophagosomes and ER-to-Golgi transport. Now, the lab is engaged in the molecular dissection of TECPR2 with the aim to determine critical interaction sites with partner proteins and cellular membranes which may coordinate the involvement of TECPR2 in trafficking and protein sorting. To this end, the team uses a range of biochemical, cell biological and proteomic approaches as well as a HSAN9 mouse model. Mechanistic insights into the role of TECPR2 have the potential to contribute to rationalizing strategies to rescue or bypass TECPR2 malfunction and develop treatment options for HSAN9 patients.
Michael Ebner (FMP, Berlin) discussed the role of phosphoinositide (PI) switches in lysosome homeostasis and damage control. Lysosomal membrane permeabilization (LMP) is a hallmark of lysosome-related diseases and can be triggered by cellular stressors. As previously shown by Tan & Finkel, LMP stimulates a phosphoinositide-initiated membrane tethering and lipid transport pathway for rapid lysosomal repair. This involves recruitment of the PI4P kinase PI4K2A on damaged lysosomes generating high levels of PI4P that in turn recruits a set of proteins that orchestrate new membrane contacts between damaged lysosomes and the endoplasmic reticulum (ER). These contacts facilitate rapid lipid transfer to damaged lysosomes to support lysosomal repair. He also discussed how members of the myotubularin family are involved in these processes (for recent review see here).
Roisin McManus (DZNE, Bonn) presented recent data on how NLRP3-mediated glutaminolysis regulates microglia in Alzheimer’s disease. In brief, loss of NLRP3 influences glutamine/glutamate related metabolism. This is associated with enhanced mitochondrial and metabolic activity and impacts microglial function leading to more significant phagocytosis of Aβ peptides. This pathway is conserved between mouse and man, and pharmacological inhibition of NLRP3 mimics this effect but it requires chronic NLRP3 inhibition.
Melania Capasso (DZNE, Bonn). In the context of aging and disease she discussed mechanisms and consequences of the observation that microglia from aged mice upregulate mTOR complex 1 signaling controlling translation, and protein levels of inflammatory mediators. By using techniques such as RiboTag, the team tries to gain a deeper understanding of mTOR1-dependent translation of genes upregulated in aging microglia and related cell types.

A short Q&A session chaired by Robert Steinfeld (Charité, Berlin) and Herman van der Putten (NCL-Stiftung) ended the meeting, also by thanking all the speakers and participants. After an evening get-together for dinner that allowed for plenty of scientific and social exchange, discussions continued next morning on opportunities for collaborations which resulted in several interesting ideas for future collaborations, and that are the topic of ongoing discussions.

We thank all the speakers, participants and sponsors for the very exciting and fruitful discussions, and we hope that some novel collaborative efforts will emerge.