What’s synuclein, got to do, got to do with it…
My Grandma had dementia. She was never formally diagnosed because she only saw a primary care doctor who was not an expert in geriatric medicine. However, the antipsychotic medication she took caused stiffness and falling and so I suspect Dementia with Lewy Bodies, a neurodegenerative disorder with clumps of a protein called α-synuclein in the brain called Lewy bodies, and motor symptoms similar to Parkinson’s Disease (PD). I remember calling her and she would tell me, “I’m here waiting for your grandfather to get home from work”, which broke my heart as Grandpa had died ten years earlier. To me, cognitive changes are among the scariest symptoms in neurodegenerative disease, including PD, because they have a profound effect on the day to day functions of the person with the disease and caregivers. High-powered lawyers with PD told me they had to quit their jobs because they could no longer handle multi-tasking. Although not everyone with PD develops cognitive symptoms, and the type of changes and severity are different for each person, this is one of the symptoms that deserves our attention as researchers. (I am avoiding the word “dementia”, according to the dictionary, dementia means “madness, insanity” and the word is not appropriate when discussing cognitive changes in PD).
The treatments for some of the motor symptoms of PD are effective enough that the non-motor symptoms have become more appreciated and are receiving more attention. It is currently unknown what causes cognitive changes, but it is unlikely to be related to loss of dopamine neurons in the substantia nigra (which cause motor difficulties) as cognitive changes are not typically improved with drugs that increase dopaminergic transmission. A couple of other WPC 2023 blogs mention the amazing recent advances in identifying genetic causes of PD. I think if we pay careful attention to the stories the genetics of PD are telling us, we can begin to figure out the biologic causes of cognitive changes and find treatments to prevent them.
The first gene important to mention is SNCA, which makes the protein α-synuclein. In 1997, the A53T mutation was discovered in an Italian family from a small town in Italy, Contursi Terme. The mutation is inherited in an autosomal dominant manner, meaning that if a person has just one copy of the mutation, they get PD. Also in 1997, Dr. Maria Spillantini discovered that Lewy bodies, clumps of proteins in the brain in individuals with PD, contain α-synuclein. As an aside, one could reasonably argue that Italians have made some of the most important contributions to science over the past several centuries (insert winking emoji here!). Since 1997, several more SNCA mutations in have been discovered, as well as duplications and triplications in the SNCA gene. Although genetic changes in SNCA cause PD they are very rare, individuals with SNCA mutations and triplications have motor symptoms, cognitive decline, and psychiatric symptoms. Relevant to cognition, one of the earliest discoveries of α-synuclein was in male zebra finches, social birds from Australia that learn to sing one song throughout their lives to defend their territory and attract females. There are changes in levels of α-synuclein while the zebra finch is learning his song, suggesting that the gene plays a role in learning and memory, a finding supported by other species including rodents. In humans, accumulation of abnormal α-synuclein, in areas of the brain related to cognition, strongly associates with cognitive symptoms.
LRRK2, which encodes leucine-rich repeat kinase 2, is a genetic cause of autosomal dominant PD. In a recent analysis by Dr. Lorraine Kalia, it was found that 67% of individuals with the most common LRRK2 mutation, LRRK2 G2019S, have Lewy bodies, and only 35% individuals with other LRRK2 mutations have Lewy pathology. Of course, it remains possible that the development of methods of detecting earlier abnormalities in α-synuclein may reveal that more of these individuals have pathologic α-synuclein. However, the simplest conclusion from this analysis is that deposits of α-synuclein are not necessary to cause PD. Of the individuals with LRRK2 mutations, those with Lewy bodies had a significant increase in cognitive decline and anxiety compare to individuals with LRRK2-PD without Lewy pathology, suggesting that Lewy pathology may be the trigger for cognitive changes.
Mutations in the GBA1 gene, which encodes for lipid metabolizing enzyme glucocerebrosidase, are also telling us important information on the cause of cognitive decline in PD. One copy of mutant GBA1 increases the risk of PD and cognitive decline. All individuals with mutant GBA1 (except one with the non-neuronopathic N370S mutation) have Lewy pathology. Again, these findings suggest a possible interaction between Lewy pathology and cognitive symptoms.
Finally, individuals diagnosed with PD at ages greater than 65 have a greater risk for cognitive decline than individuals diagnosed with PD at earlier ages. Over 90% of late onset PD individuals have abnormal α-synuclein aggregates. Individuals with recessive mutations in genes encoding DJ-1, PINK1, and Parkin, which cause early onset PD, have not shown Lewy pathology to date. Thus, the combination of changes in α-synuclein and aging could be an important factor for cognition.
In conclusion, research is needed to determine the pathological trigger for cognitive impairments in PD. However, findings that not all PD patients have Lewy pathology is critical in that it suggests that pathologic α-synuclein does not cause PD but may play a role in non-motor symptoms. A major recent advancement is the development of assays to detect abnormal α-synuclein in skin biopsies and cerebrospinal fluid using a method to amplify these aggregates, called α-synuclein amplification assays (SAA). Such assays will be invaluable for determining who has PD with Lewy pathology and how best to treat these individuals. For example, inhibitors of LRRK2 kinase activity could be used to treat those with PD without Lewy pathology. For those positive for abnormal α-synuclein, treatments preventing formation of aggregates could prevent cognitive decline. Paying close attention to what the data is telling us will help us develop personalized therapies for the diverse symptoms of PD.
Laura Volpicelli-Daley, PhD is an Associate Professor of Neurology, Parkinson Association of Alabama Endowed Professor at the University of Alabama at Birmingham. She is a speaker at the WPC 2023 Congress. View the Scientific Program here.
Twitter: @lvolpic
Ideas and opinions expressed in this post reflect that of the author(s) solely. They do not necessarily reflect the opinions or positions of the World Parkinson Coalition®