What do Gaucher’s disease, gout, and amyloid plaques have in common? For researchers at the MGH, each of them may shed light on the causes and treatment of Parkinson’s disease.  In the scope of PD research across disciplines and institutes, “we have built a thread from the science to the therapeutics,” says Michael Schwarzschild, MD, PhD.

Lysosomes Emerge as Key Mediators of Neuronal Health and Disease

Development of therapies for neurodegenerative diseases such as Parkinson’s disease has been slowed by absence of rigorously validated targets, says Dimitri Krainc, MD, PhD, of the MassGeneral Institute for Neurodegenerative Disease (MIND) and Associate Professor of Neurology at Harvard Medical School. That has led to a relative absence of ideas about how to protect neurons in the disease, and to disappointing results in the few neuroprotective trials there have been. But a recent set of discoveries may be poised to change that.

Mutations in the gene for the enzyme glucocerebrosidase (GBA) are best known for causing the childhood lysosomal storage disorder, Gaucher’s disease, but they are also the most common genetic risk factor for PD. GBA is a lysosomal enzyme, and loss of lysosomes causes havoc in the cell’s protein and organelle recycling system. In laboratory models, lack of GBA leads to development of protein aggregates containing alpha-synuclein, the pathologic hallmark of PD in humans. Without lysosomal activity, clearance of damaged mitochondria appears to be impaired, further exacerbating stress within the cell. “Lysosomes have to work in order for neurons to do their job,” Dr. Krainc says. “We propose, therefore, that strategies to specifically upregulate lysosomal function will be beneficial in neurodegenerative disorders.”

Preliminary results from lab models indicate that elevating GBA in the brain can reduce the level of alpha-synuclein accumulation. Further work will be needed to determine if GBA itself is the best target, but the spotlight it has shown on lysosomes in neurodegeneration is perhaps just as important. Lysosomes may become an important target for therapeutic trials, Dr. Krainc says, and improvements in lysosomal activity an important biomarker in those trials. “If we can show a drug is having an effect on these in a small trial, then we have a validated target and a biomarker for affecting that target. These are the bottlenecks of drug development that we have to address to move the field forward, and this pathway has the potential to overcome these two bottlenecks. If you are a patient, this is what you hope for.”

Can Raising Urate Protect Against Parkinson’s Progression?

Michael Schwarzschild, MD, PhD, doesn’t want to give anyone gout. But he does wants to know if raising blood urate—a risk factor for gout—can delay the progression of Parkinson’s disease. “It is a bit heretical,” he admits, but epidemiologic studies have shown conclusively that higher-than-average urate reduces the risk for developing Parkinson’s disease. “We wanted to see if, rather than just observing that difference, we can generate that difference,” he says. So Dr. Schwarzschild, a member of MIND and Associate Professor of Neurology at Harvard Medical School, and colleagues in the Parkinson Study Group, an international research consortium, are conducting an intervention trial, to see if raising urate is safe in early PD, and to determine how best to test if it can delay patients’ need for symptomatic therapy. Patients with low urate at diagnosis are enrolled to receive placebo or inosine, a urate precursor, titrated to the putatively protective levels seen in the population studies. Results from the trial are due out in late 2013.

The strength of MIND, Dr. Schwarzschild says, is its interdisciplinary make-up, with molecular neurobiologists such as himself collaborating with epidemiologists and geneticists, and specialists in Parkinson’s disease sharing ideas with their counterparts in Alzheimer’s disease, Huntington’s disease, and others, “to pick up clues that would have been much harder to identify if we were all working in isolation.”

Amyloid in PD Predicts Cognitive Decline

Dementia in the context of Parkinson’s disease is too often overlooked, according to John Growdon, MD, Professor of Neurology at Harvard Medical School and attending neurologist at Mass General. “In the past, Parkinson’s disease has always been viewed as a primary motor disease, but information has emerged that about 80% of people with PD are demented at the time they die.” Despite the significance of dementia in the disease, motor symptoms have remained the focus of most treatment research. Dr. Growdon has worked to call attention to dementia in PD, and to figure out why it is so common.

Different pathologies coexist with the alpha-synuclein-containing Lewy bodies that are characteristic of PD. Whether these other pathologies are “part and parcel of the disease, or are additional hits, is unknown,” Dr. Growdon says. For instance, he notes, the majority of PD patients with dementia have amyloid pathology at autopsy.

To determine what the implications of amyloid in PD might be, he and his colleagues prospectively imaged amyloid in a group of non-demented PD patients over several years. They found that baseline amyloid predicted cognitive worsening over time, without any effect on motor decline, suggesting that amyloid pathology is operating independently. “The practical consequences of this observation are that whatever anti-amyloid therapies work that are being developed primarily for Alzheimer disease—a very big and active area for many pharmaceutical companies—will have immediate relevance to PD,” Growdon says.

Clinical Trials & Research Publications

Mazzulli JR, Xu YH, Sun Y, Knight AL, McLean PJ, Caldwell GA, Sidransky E, Grabowski GA, Krainc D. Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell. 2011 Jul 8;146(1):37-52. doi: 10.1016/j.cell.2011.06.001. Epub 2011 Jun 23.

Usenovic M, Knight AL, Ray A, Wong V, Brown KR, Caldwell GA, Caldwell KA, Stagljar I, Krainc D. Identification of novel ATP13A2 interactors and their role in α-synuclein misfolding and toxicity. Hum Mol Genet. 2012 Sep 1;21(17):3785-94. doi: 10.1093/hmg/dds206. Epub 2012 May 29. 

Cipriani S, Chen X, Schwarzschild MA. Urate: a novel biomarker of Parkinson's disease risk, diagnosis and prognosis. Biomark Med. 2010 Oct;4(5):701-12. doi: 10.2217/bmm.10.94. Review. 

McFarland NR, Burdett T, Desjardins CA, Frosch MP, Schwarzschild MA. Postmortem Brain Levels of Urate and Precursors in Parkinson's Disease and Related Disorders. Neurodegener Dis. 2013 Feb 28. [Epub ahead of print] 

Gomperts SN, Locascio JJ, Rentz D, Santarlasci A, Marquie M, Johnson KA, Growdon JH. Amyloid is linked to cognitive decline in patients with Parkinson disease without dementia. Neurology. 2013 Jan 1;80(1):85-91. doi: 10.1212/WNL.0b013e31827b1a07. Epub 2012 Dec 12. 

Farabaugh AH, Locascio JJ, Yap L, Fava M, Bitran S, Sousa JL, Growdon JH. Assessing depression and factors possibly associated with depression during the course of Parkinson's disease. Ann Clin Psychiatry. 2011 Aug;23(3):171-7.