08 Jan 2025

Barbara Lazarus’ two sons, David and Daniel, were healthy and active kids, but things changed in their early 20s. David developed severe psychiatric symptoms, which were diagnosed as schizoaffective disorder. Daniel, meanwhile, began having tremors and memory loss that mystified physicians. “My husband and I would look at each other and say, ‘Really, both of them?’” Lazarus recalled.

It never occurred to the family that both brothers could have the same rare genetic condition. In 2017, neurologists at New York Presbyterian/ Columbia University’s movement clinic diagnosed Daniel with Niemann-Pick disease Type C (NPC): a lysosomal storage disorder caused by NPC1 mutations. Genotyping revealed that David had an identical mutation. NPC disease is usually fatal within 10 years and most often begins in early childhood, but the Lazarus brothers are a rare exception. “We were blindsided,” Barbara Lazarus said. “We never thought it would be that significant of a diagnosis.”

How can brothers with the same mutation have such different symptoms? A mouse study published December 4, 2024, in Science Translational Medicine offers some clues. Scientists led by Sabina Tahirovic, DZNE, and Matthias Brendel, at Ludwig-Maximilians University, both in Munich, found that eliminating Npc1 from just microglia is sufficient to cause rampant neuroinflammation and recapitulate many of the neurological characteristics of NPC. The study suggests that inflammation, itself a heterogenous phenomenon, explains NPC’s myriad symptoms. The findings also support the hypothesis that schizophrenia-like symptoms, which are more common in late-onset than childhood NPC, might be caused by microglia overzealously pruning synapses.

A broad range of clinical symptoms makes NPC notoriously difficult to diagnose. David and Daniel had had health problems for many years before being tested for NPC1 variants. Common symptoms include dementia, and loss of motor control, hearing, or vision. Both brothers’ cognitive abilities have slowly declined in the eight years since their diagnoses, but their other symptoms remain distinct. “It's always been a big head scratcher for me,” Barbara Lazarus told Alzforum.

The heterogeneity mystifies scientists, too. They know that hundreds of different NPC1 mutations can cause the condition but, as with Daniel and David, specific mutations don’t always predict specific phenotypes. “There must be other disease-modifying factors,” Tahirovic said.

One such potential factor is the immune system, particularly microglia that respond to brain lesions and can exacerbate inflammation. In their study, first author Lina Dinkel and colleagues found that inactivating Npc1 only in myeloid cells could recapitulate many aspects of the disease. Their findings indicate these cells play a key role in initiating NPC pathology rather than simply responding to neuronal damage.

Previous research has shown that knocking out Npc1 across the mouse brain mirrors human phenotypes, but the respective roles of different cell types were unclear. To study how microglia fit in, Dinkel and her colleagues created a myeloid-specific Npc1 knockout mouse line. Unlike mice that completely lack Npc1, which die young and have fast-progressing neurodegeneration, these conditional knockout mice lived for up to 12 months and their neurons degenerated slowly.

What was going on in their brains? Microglia didn’t seem to cause the characteristic demyelination seen in NPC disease. In vitro, however, both Npc1 knockout mouse microglia and human microglia carrying a common NPC1 mutation engulfed more myelin, which then accumulated in their late endosomes and multivesicular bodies. Lipid accumulation in lysosomes and in LE/MVBs is a hallmark of NPC1, a lysosomal storage disorder.

Indeed, compared to microglia from control mice, those in the knockouts contained more cholesterol and lower levels of cholesterol metabolites, such as cholesteryl esters, suggesting their ability to transport and metabolize lipids was impaired.

PET imaging of the animals’ brains with the tracer 18F-GE-180 picked up more translocator protein 18 kDa (TSPO), a marker of microglial activation (image at right), while FDG-PET revealed reduced glucose metabolism, a marker of neural activity that also falls in people with NPC.

In keeping with this, the mouse brains and blood contained high levels of the neurodegeneration biomarker neurofilament light (image below). GFAP, an indicator of astrocyte activity, also surpassed levels in controls. Lower levels of P2RY12, a marker of microglial homeostasis, and SLC6A5, a marker of healthy neuronal function, suggested a struggle within the brain.

Ralph Nixon, New York University, called the paper “wonderful.” While many have long suspected that microglia were involved in the disease’s early stages, this study pinpoints their role in causing specific problems, such as impaired glucose metabolism, Nixon said. To his mind, the findings suggest microglia help drive NPC from the start, rather than simply mopping up after neurons become damaged.

But Barry Boland, University College Cork, Ireland, is not convinced the study proves that hyperactive microglia are main drivers of pathology. The knockout removed NPC1 from other myeloid cell types too, creating lipid storage problems in cells such as peripheral blood macrophages, which could contribute to the phenotype, he noted. Beyond hyperactivity, impaired microglial phagocytosis could also cause stress and damage neurons via other means.

Moreover, the mice lacked some characteristics of human NPC, such as neuronal loss in the cerebellum and demyelination at late stages of the disease. Boland thinks these human phenotypes may be caused by NPC1 loss in neurons or other cell types in addition to microglia. “It leads to interesting questions about the interplay [between microglia and neurons],” he said. Tahirovic and colleagues acknowledge the model’s limitations.

Even so, they reasoned that if excessive phagocytosis drives neurodegeneration in people, slowing down phagocytosis should reverse neurodegeneration. To test this idea, they measured TSPO in blood macrophages from three people with NPC enrolled in a clinical trial for the recently approved drug N-acetyl-leucine. NALL is thought to work by stabilizing cell membranes to improve glucose metabolism and lysosome function. Mass spectrometry analysis showed that TSPO levels in blood macrophages dropped after six weeks of NALL treatment (image below).  In a phagocytosis assay using Aβ as a substrate, macrophages isolated after the treatment engulfed less Aβ than did those isolated before, suggesting that the drug might have quieted overactive phagocytic cells.

Tatiana Brémovà-Ertl, University Hospital Bern, Switzerland, and Michael Strupp, University of Munich, ran pivotal clinical trials of NALL. They were pleased, but unsurprised, to see its effects on markers of phagocytosis. They are currently studying whether NALL slows other neurodegenerative disorders where pathological proteins aggregate and lysosomes malfunction, such as Parkinson's. A pilot study in two people with disordered REM Sleep, considered a prodrome to PD, looks promising, (Oertel et al., 2024; Balint and Bhatia, 2024). The researchers are awaiting approval to conduct a large clinical trial in Parkinson's and Alzheimer's diseases.

Treatment trials with NALL and other drugs for lysosomal disorders might benefit from tracking efficacy with TSPO, Nixon said. Indeed, with Brémovà-Ertl and Strupp, Tahirovic and colleagues scanned the brains of five adults, age 27-58, with NPC for TSPO. All had more TSPO across their brain than did healthy age-matched controls, suggesting this might work. Separately, their TSPO levels were also higher than in people with AD or tauopathies.

Right now, TSPO-PET imaging can only be performed at specialized centers. Tahirovic said that developing a blood-based measure of TSPO could be a game-changer. A biomarker for NPC is especially needed because the disease and its trajectory vary so widely between people, and because physicians rarely think to look for it. Abnormal TSPO values in a child’s blood panel, for instance, could be a tip-off to sequence the NPC1 gene, she said. It could also circumvent a nagging problem with TSPO PET, namely that in some people’s brains TSPO ligands bind with higher affinity due to a single amino acid change in the transporter.

Lazarus also wants a biomarker. She suspects NPC disease might be more common than people realize. “Someone like David who only had psychiatric issues could go forever with the diagnosis of schizophrenia and his little bit of tremor would be attributed to the psychiatric medications,” she said.

Daniel, who depends on his parents for help with daily activities, is currently taking NALL. David works in construction and is taking arimoclomol, a recently approved small molecule that helps prevent protein misfolding and reduces lysosomal stress (Mengel et al., 2021). Lazarus told Alzforum that she is trying to get insurance to pay for both her sons to take these drugs, each of which cost tens of thousands of dollars per month.

Lazarus hopes research into the parallels between NPC and other dementias will open more doors, even if it’s not in time for her sons. “We want the best possible outcome in quality of life and trying to provide some level of dignity,” she said. “But we know [these drugs are] not a cure: They lost a lot and are not going to regain what was lost.”—Sara Reardon

Sara Reardon is a freelance writer in Bozeman, Montana.

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

1. Oertel WH, Janzen A, Henrich MT, Geibl FF, Sittig E, Meles SK, Carli G, Leenders K, Booij J, Surmeier DJ, Timmermann L, Strupp M. Acetyl-DL-leucine in two individuals with REM sleep behavior disorder improves symptoms, reverses loss of striatal dopamine-transporter binding and stabilizes pathological metabolic brain pattern-case reports. Nat Commun. 2024 Sep 2;15(1):7619. PubMed.
2. Balint B, Bhatia KP. Small Molecule, Big Hope-Can Acetyl-DL-Leucine Reverse Parkinson's Disease?. Mov Disord Clin Pract. 2024 Dec 27; Epub 2024 Dec 27 PubMed.
3. Mengel E, Patterson MC, Da Riol RM, Del Toro M, Deodato F, Gautschi M, Grunewald S, Grønborg S, Harmatz P, Héron B, Maier EM, Roubertie A, Santra S, Tylki-Szymanska A, Day S, Andreasen AK, Geist MA, Havnsøe Torp Petersen N, Ingemann L, Hansen T, Blaettler T, Kirkegaard T, Í Dali C. Efficacy and safety of arimoclomol in Niemann-Pick disease type C: Results from a double-blind, randomised, placebo-controlled, multinational phase 2/3 trial of a novel treatment. J Inherit Metab Dis. 2021 Nov;44(6):1463-1480. Epub 2021 Sep 7 PubMed.

Further Reading

News

1. Lysosomal Diseases: Stepping Stones to Gene Therapy for Alzheimer’s? 5 Dec 2019
2. Could Targeting CD22 Restore Microglial Lysosome Trafficking? 7 Dec 2021
3. Microglial Transplants Reverse Age-Related Pathology in Mice 28 Jun 2024
4. Do Overloaded Microglia Smother Stressed Neurons? 14 Oct 2024