Parkinson’s Disease

See also Microglial cells under Immune Cells

Introduction:

Parksinson’s diease (PD) is a progressive neurological disorder known for its characteristic motor symptoms, which include tremor, regidity, and slowness of movement. Among these, rest or resting tremor (RT) – a shaking that occurs when muslces are relaxed -is one of the most recognizable yet least understood. (“Parkinson’s symptomk resting remor, relates to dopamine in unexpected way” Noember 18, 2024.)

PD is the second most common neurodegeneration disease. (Fu, “Mutant mice with rod-specific VPS35 deleted exhibit retinal alpha-synuclein pathology-assocaited degeneration” (August 2023).

Symptoms:

Impaired vision:

More than 80% of PD patients develop early visual symptoms (e.g., impaired visual acuity, spatial contrast sensitivity, depth perception, and color vision. Also, retinal thinning due to the loss of retinal nuerons is seen in early human PD. Fu, “Mutant mice with rod-specific VPS35 deleted exhibit retinal alpha-synuclein pathology-assocaited degeneration” (August 2023).

Pathology:

Alpah-synuclein (alpha-Syn) and other misfolded proteins:

Parkinson’s Disease (PD) is a neurodegenerative disease caused by progressive accumulation of abnormal intracellular aggregates of alpha synuclein (alpha-Syn) protein existing as Lewy bodies, the pathological hallmark of the disease. Lewy bodies first appear in the olfactory bulb and medulla and gradually spread to midbrain, at which time, the first motor sign of PD appear. Concomitantly, inflammatory responses form resident microglia result in T-cell recruitment, setting off an exacerbating inflammatory cascade. together, these events lead to the progressive demise of nigrostriatal dopaminergi neurons, resulting in the classical clinical signs of bradkykinesis, rest tremor and regidity. Symptomatic relief is provided by dopamine replacement, but the underlying disease process continues unabated. Cao (US Patent Application No: 2017/0196948, published as US 10,653,759)

Structurally, human alpha-Syn is an intrinsically disordered 140 amino acid long protein consisting of three distinct regions: an N-terminal region (residues 1-60) which forms a helical structure and interacts with the cellular membrane, a central highly aggregation-prone non-Abeta component region (residues 61-95) and a C terminal region (residues 96-140) that is highly enriched in acidic residues and prolines. Cao (US Patent Application No: 2017/0196948, published as US 10,653,759)

Preclinical evidence has suggested that other misfolded proteins including

hyperphosphorylated tau, prior proteins, huntingtong, TAR DNA binding protein 43, and mutant superoxide dismutase 1 (SOD1) can also be targeted for immunotherapeutic strategies Cao (US Patent Application No: 15/313,810, published as US 10,653,759)

Alpha-Synuclein has been identified as the major component of such inclusions and it is found in the brains of PD patients and patients wtih other degenerative disorders such as the LB variant of Alzheimer’s disease.

Dodel (US 2013/0052200) discloses naturally occurring autoantibodies that bind to alpha-Synuclien from human sera and commercial IgG preparations (IVIG).

Alpha-synuclein is a protein which builds up in PD patients. (Morreale, “Cancer Immunotherapy applied to Parkinson’s Disease” June 20, 2024). Aggregates of the brain protein alpha-synuclein (alpha-Syn) are generally considered to have a major role in the pathological development and progression of PD. Cao (US 10,653,759)

AlphaSyn, which is important for synaptic vesicle (SV) recylng is especially susceptible to misfolding and forming amorphous aggregates and fibrils. Also critical for SV recyling is the molecular chaperon HSC70 (or HSPA8). HSC70 uncoats clathrin-coated visles in presynpatic terminals, facilties the proper folding of newly translated proteins, and escorts misfoled proteins, such as alphaSyn, for selective autophagic degradation. Fu, “Mutant mice with rod-specific VPS35 deleted exhibit retinal alpha-synuclein pathology-assocaited degeneration” (August 2023).

–Associated Proteins with Alpha-Synuclein:

Dawson and others have discovered that a cell surface marker, Aplp1, binds to Lag3 and drives PD. Interestingly, Aplp1 has been associated with the spread of alpha-synuclein throughout the brain once binding with Lag3. Aplp1 bound to Lag3 allows brain cells to accumulate clumps of alph-asynuclein, which results in cell death promoting PD symptoms. The binding of aplp1 and Lag3 suggests that by targeting this interaction, PD symptoms could be significantly delayed. This discovery is exciting because Lag3 checkpoint inhibitors is already FEDA approved and could reasonably apply to PD patients in combination with other treatments. Researchers discovered that mice lacking Aplp1 and Lag3 had 90% reduction of alpha-synuclein adsorption. Anti-Lag3 also prevented the adsorption of alpha-synuclein and significantly slowed PD symptoms. (Morreale, “Cancer Immunotherapy applied to Parkinson’s Disease” Immunology, June 20, 2024)

Dopamine levels:

Parkinson’s Disease (PD) is a degenerative neurological condition linked to reduced dopamine levels in the brain, caused by degeneration and death of “dopaminergic” neurons. PD is the second most common neurodegenerative disorder globally as it affects about 1% of the population over 65 years old worldwide. It is clinically characterized by resting tremor, slowness of movement, muscular rigidity and impairment of postural reflexes. The progressive loss of dopaminergic neurons in the substantin migran and formation of fibrillar cytoplasmic inclusions term “Lewy bodies” and “Lewy neurites” are the nueropathological hallmarks of PD.

However, a new study from the Champalimaud Foundation, led by scientifists at the Nueral Circuits Dysfunction Lab in collaboration with the Neuropsychiatry and Nuclear Medicine Labs, indicated the preserved dopamine in certain brain regions may actually contribute to tremor symptoms, challenging common beliefs. Paradoxically, they discovered that patients who exhibit tremor have more dopamine preserved in the caudate nucleus, a part of the brain important for movement planning and cognition. This challenges traditional understanding of how dopamine loss related to PD symptoms and highlights the importance of looking beyond general classifications in PD and underscores the need for more nuanced approaches informed by underlying biology, which could ultimately hep to inform on therapeutic strategies. Dopamine loss in brain regions including the putamen, associated with movement regulation, is a well established hallmark of PD. Dopamine loss is also necessary for rest tremor to be present. However, while some patients experience significant tremor relief with dopamine replacement therapies, such as L-DOPA, others see little to no improvement, or even a worsening of symptoms. This suggests that the link between dopamine depletion and RT is more complex than a simple DA dose dependency model, the term noted. Resting tremor (RT) is a Parkinson’s disease symptom with an unclear relationship to the dopaminergic system. By combining imaging data with measurements from these sensors, they observed a clear link between dopamine function in the caudate nucleus and global severity of resting tremor. The analysis suggested that the more dopamine activity preserved in the caudate, the stronger the tremor. An in more intriguing finding was that the more dopamine was preserved in the caudate on one side of the brain (each hemisphere has its own caudate), the more tremor there was on teh same side of the body. (usually, each side of the brain controls movement on the oppsite side of the body) The study also noted that not all dopamine cells are alike. They have different genetic maekups, connections and functions. This means that which cells a patient loses or keeps could affect theri symptoms. For example remor might be tied to the loss or preservation of specific dopamine populations that connect to certain brain areas. This variation in cell type loss could further expalin the wide range of symptoms among PD patietns. “Parkinson’s symptomk resting remor, relates to dopamine in unexpected way” Noember 18, 2024.)

Leucine-rich repeat kinase 2 (LRRK2): is a protein implicated in the pathogenesis of Parkinson’s disease and progressive supranuclear palsy (PSP). Increased activity and expression of LRRK2 are linked to the development of these neurological diseases.

Microglia Activation: begins early and persists throughout the course of PD. (“Chen, “microglia in neurodegenerate diseases: mechanism and potential therapeutic targets” Signal Transduction and Targeted Therapy (2023) 8: 359).

Despite the potential role of neuroinflammation in PD, no specific microglial phenotype has been associated with PD. Gal-3 and proinflammatory factors in primary microglia in the presence of different forms of SYN has, however, been found (Venero, “Galectin-3, a rising star in modulating microglia activaiton under conditions of neurodegeneration” (2022)

–Galectins (e.g., Gal-3):

The advent of high-throughput single-cell transcriptomic analysis of microglia has revealed different phenotypes that are inherently associated with disease conditions. A common feature of some of these activated phenotypes is the upregulation of galectin-3 (Gal-3) which is a pleiotropic protein that binds to beta-galactoside residues present in glycoproteins. Gal-3 is mainly expressed and released in the damaged brain by reactive microglia and interacts with immune receptors like TREM2 and TLR4. In general, galectin molecuels are based on conserved beta-galactoside-binding sites found within their characteristic 130 mino acid carbohydrate recognition domains. This conserved domain binds to geta-galatosides with different specificities and affinities. Some of these lectins are expressed constitutively, while others are expressed upon stimulation. Improtantly, glycosylation patterns change under physiological and pathogenic conditions impacting galectin functions. Among the 15 members of the galectin family, only Gal-1, Gal-3, Gal-4, Gal8 and Gal9 have been found to be significanlty expressed in the brain, wehre theri functions are still little understood. Gal-3 is assocaited with activated microglia since homeostatic microglia do not expresss Gal-3. Gal-3 is known to medaite TLR4 induced proinflammatory response. In addition, Gal-3 has the ability to initiate the phagocytic response. (Venero, “Galectin-3, a rising star in modulating microglia activaiton under conditions of neurodegeneration” (2022).

Retinal Abnormalities:

–Retinal thickness:

Although the mechanism underlying retinal cell death in PD is unkown, retinal thickness, determed by spectrum-domain optical coherence tomography (SD-OCT) has been used as a biomarker during human trials of PD treatments. Fu, “Mutant mice with rod-specific VPS35 deleted exhibit retinal alpha-synuclein pathology-assocaited degeneration” (August 2023).

Lewy body (LB) inclusions are the pathologic hallmark of PD and have been observed in PD patient retinas, alpha-synuclein, particulalry the phosph(S219)-alphaSyn (“P-alphaSyn) is highly expressed in LB inclusions. A positive correlation between the desnity pf P-alphaSyn-labeled inclusions/nuerites in retinal ganglion cells of postmortem PD pateint eyes and their clinical grading scale has been reported. (Fu, “Mutant mice with rod-specific VPS35 deleted exhibit retinal alpha-synuclein pathology-assocaited degeneration” (August 2023).

Endolysosomal Abnormalities:

–Mutated VPS35:

A mutation of VPS35, the core component of the retromer complex that also contains VPS26 and VPS29 causes a familial form of PD (PARK17). VPS35 deficiency has also been linked to Alzheimer’s. Retromer, predominaly residing on the early endosomes, is a master conductor that srots cargoes to the trans-Golgi network, cell surfaces, late endosome (LE) or lysosome (Lys). The degradative compartments, LE and Lys, both ahve an acidic lumen and express the common markers Lamp1 and Lamp2. However, LE has a unique multivesicular lumen that also expressed the specific marker CD63. A conditional mouse mutant line where the Vps35 gene was selectively deleted in rods developed early rod terminal loss well in advance of rod cell death and exhibited prominent P-alphaSyn and uqiquitin positive LB like includsion. ETOLLAVIS

Genetic Variants:

Although therapeutic modificaiton of several genetic targets has reached the clinical trail stage, a major obstacle in conducting these trials is that PD pateints are largely unaware of their genetic satus and, therefore, cannot be recruited. Expanding the number of investigated PD related genes and genes related to disorders with overlapping clinical features in large, well phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene targeted clinical trails. (Hanseen, “Relevance of genetic testing in the gene-targeted trails era: the Rostock Parkinson’s disease study” Brain 2024: 147; 2652-2667).

The genetic landscape of PD and related phenotypes is multifaceted. Even when considering only monogenic causes of classical PD, pathogenic variants in seven genes (LRRK2, PRKN, PINK1, SNCA, PARK7, VPS35 and CHCHD2) are implicated. Furthemore, heterozgous changes in GBA1 are a strong risk factor for PD. In addition, >30 other more complex monogenic movement disrders may present with atypical parkinsonism or may have parkinsonism as a prominent or even predominant clinical feature in at elast a subset of patients. (Hanseen, “Relevance of genetic testing in the gene-targeted trails era: the Rostock Parkinson’s disease study” Brain 2024: 147; 2652-2667)

The ROPAD study is an observational clinical study which assesssed the frequency and type of pathogenic variants in known PD related genes adn genes realted to other movement disorders or dementia in a multicentry, international setting. The study is registed at clinicaltrials.gov (NCT03866603) and is a collaboration between CENTOGENE GmbH (Rostock, Germany), the University of Lubeck and Denali Therapeutics (San Francisco, CA).

Treatment:

Introduction: Treatments to manage Parkinson’s disease (PD) symptoms include medications that target depression, tremors, pain, and pysical movement. Most of the medications increase the levels of dopamine in the brain, which is a chemical that helps relay information from your brain to the rest of your body. However, new therapeies are being investiated to better control and slow down the progression of PD (Morreale, “Cancer Immunotherapy applied to Parkinson’s Disease” June 20, 2024).

There are about 20 therapies on the market that address the syptoms of Parkinson’s diease. However, currently there are no dieasese modifying treatments becasue the underlying cause of the disease is still unclear. (McKenzi, “7 Alzheimer’s and Parkinson’s Programs Discarded in 2024” BioSpace, November 4, 2024).

L-3,4-Dihydroxyphenylalanine (L-DOPA): synthesized from L-tyrosine, is a direct precursor to dopamine. L-DOPA is the gold standard treatment for PD, given orally alongside decarboxylase inhibitors (e.g., benserazide) to enhance bioavaiability. L-DOPA crosses the blood-brain barrier and temporarily resides in nerve terminals before its rapid conversion to DA. However, its daily pulsatile-like delivery is associated with complications. (Padhi, “Biotengineered gut bacteriu syntehsizing levodopa alleviates motor deficits in models of Parkinson’s diease” Cell Host & Microbe 33, 1837-1854, 20250)

Dopamine Receptor Stimulators:

–Rotigotin: is a dopamine receptor stimulator that has been used to treat Parkinson’s since the 1990s.

A rotigotine transdermal path is sold by UCB Manufacturing.

–Tavapadon (Cerevel Therapeutics aquired by Abbvie) is a partial agonist that activates dopamine D1/D5 receptors, which regulate motor activity. It is taken once daily and can be used as a monotherapy or in combination with other drugs.

–Vyalev (Abbvie) combines two drugs that help boost dopamine levels in the brain and keep symptoms under control for a full 24 hours. Instead of taking pills throughout the day, this treatment is delivered through a small pump that continuously injects the medication under the skin. This new treatment offers an alternative to oral medications, which can become less effective as Parkinson’s progresses. The most common side effects include skin reactions where the injection is given, involuntary movements (dyskinesia), and hallucinations (seeing or hearing things that aren’t there).

Conversion of Precursors into Dompamine

levodpa: is taken up by brain neurons and converted to dopamine. It is taken orally and is the standard treatment for Parkinsons. Unlike dopamine itself, levodopa can cross the blood-brain barrier, which is a protective layer that regulates what substances enter the brain. Once in the brain, levodopa is converted into dopamine by an enzyme called aromatic-L-amino-acid decarboxylase (AADC). This process primarily occurs in the surviving dopaminergic neurons, but also in other cells in the brain, such as serotonergic neurons.

Levodopa eventually loses its efficacy as neurons continue to die.

–Conversion of Foslevodopa into Dopamine:

—-Produodopa (Abbvie): is a combination medication containing foslevodopa and foscarbidopa. Foslevodopa is converted into levodopa in the body, which increases dopamine levels, similar to how levodopa tablets work. Foscarbidopa helps enhance the effectiveness of foslevodopa and reduces its side effects.

Produodopa is primarily intended for individuals with advanced Parkinson’s who are experiencing significant motor fluctuations, such as “on” and “off” periods, and whose symptoms are not well-controlled with other therapies

While Produodopa (foslevodopa/foscarbidopa) helps increase dopamine levels in the brain, it does not directly stimulate dopamine receptors. It works by being converted into levodopa, which then increases dopamine levels, and by utilizing foscarbidopa to enhance levodopa’s effectiveness and reduce its side effects. Dopamine agonists, on the other hand, directly stimulate dopamine receptors.

Foslevodopa is converted into dopamine, a neurotransmitter crucial for movement control, which helps manage Parkinson’s symptoms like tremors and stiffness. Foscarbidopa enhances the effect of foslevodopa and reduces its side effects.

Probiotics:

Gut microbes function as natural chemical factories, constantly producing metabolites in response to environmental cues. This can be leveraged to overcome drug level fuctuation faced by Parkinson’s patietns. Developing living drugs has implications for treating neurological and related gastrointestinal diseases, such as Crohn’s.

–Engineering Gut Microbes for Delivery of Levodopa to the Brain:

—-Escherichia coli Nissle 1917 (EcN): Researchers at the Isakson Center for Neurological Disease Research have engineered the probiotic bacterium Escherichia coli Nissle 1917 as a drug delivery system that continuously produces and delivers the gold standard Parkinson’s drug Levodopa (L-DOPA) which is converted to dopamine in the brain. The E. coli Nissle strain was chosen for its century long record of safely treating gastrointestinal disorders in humans. A single dose of Chem L-DOA + BZ increased brain DA in C57 mice, but only up to 8 her whereas a single dose of the EcNL-DOA + BZ robustly increased brain straiatal DA concentration at 8 and 16 h. (Padhi, “Biotengineered gut bacteriu syntehsizing levodopa alleviates motor deficits in models of Parkinson’s diease” Cell Host & Microbe 33, 1837-1854, 20250)

Alpha-Synuclein Inhibitors:

–Anti-alpha-synuclein:

Cao (US Patent Application No: 15/313,810, published as US 10,653,759 and 10,155,030B2; see also PCT/US2015/032453 published as WO2015/179867) discloses methods of protecting against dopaminergic neuron cell death which includes administering an anti-alpha-synuclein peptide to a subject in need thereof, where dopaminergic neurons are protected from cell death due to alpha-synuclein mediated neurodegeneration. In preferred dmeobdiments, the anti-alpha-synuclein peptide anitibody is specific for the N-temrinal region of the alpa-synuclein protein.

It has also been reported that anti-alpha-Syn mAbs directed against the C terminal of alpha-Syn enhanced the clearing of intracellular alpha-Syn aggregates. Cao (US Patent Application No: 15/313,810, published as US 10,653,759)

–Antisense oligonucleotides against alpha-synuclein:

Denali Therapeutics has developed an antisense oligonucleotide agaisnt alpha-synuclein and a novel devliery method to get it across the blood-a transport vehicle that carries the antisense oligo into the brain by binding to the transferrin receptor, which is expressed in the vasculature of the brain, to shuttle the iron-carrying protein transferrin into the brain. The transport vehicle binds to the transferrin receptor and hijacks that transport route to bring drugs effectively into the brain. The platform has been clinically validated in a Phase I/II trail of enzyme therapy for lysosomal storage disease.

Leucine-rich Repeat Kinase 2 (LRRK2) Inhibitors:

–Proteolysis-Targeting Chimeras (PROTACs): are an emerging therapeutic approach for neurodegenerative diseases like Parkinson’s, by targeting degrading disease causing proteins such as LRRK2. PRTOACs are molecuels designed to induce the degradation of specific proteins by recruiting the body’s natural protein degradation machinery, the proteasome.

Arvinas ARV-102 (a novel orgal PROTAC designed to garget LRRK2 and currently in phase 1 clinical studies. It is designed to cross the blood-brain barrier and target LRRK2.

Vaccines:

—-DC Vaccines:

Dendritic cell (DC) vaccination is a cell based therapy that elicits an immune response by using antigen-loaded DCs as the vehicle for immunization. DCs loaded with peptide directly interact with the immune system without eliciting generalized inflammation that typically occurs in adjuvant-containing vaccines. Moreover, peptide sensitized DC vaccines trigger a longer laster antigen-specific T cell response unlike the shorter respones to traditional vaccines. Cao (US Patent Application No: 15/313,810, published as US 10,653,759)

—-Against Alpha-Syn:

Antigen sensitized DCs have been used as vaccines for treating PD. For example, Cao (US Patent Application No: 15/313,810, published as US 10,653,759) discloses a DC vaccine against alpha-synuclein. In some embodiments, more than one antigen sensitized DC is utilized in the mixture of compositions. In certain embodiments DCs sensitived with full lengh rh-alpha-Syn or with peptide fragments from h-alpha-Sun are effective in triggering the generation of anti-alpha-Syn antibodies in a Tg alpha-Sun mouse model of synucleinopathy.

—-Cell fragments from Antigen-sensitized immature DCs:

disclose using cell fragments derived from immature DCs

Autologous Cell Therapy to replace lost neurons:

Aspen Neurosciences is developing an autologous cell therapy to replace neurons and reestablish the connections that have been lost. This is advantageous because by the time patients are diagnosed with Parkinson’s, 50% of their dopamine neurons are gone. Allogeneic cell therpaies have the disadvantage that the recipient’s immune system will attack the new cells as foregin. Autologus therapies, by contrast, are made form the patient’s own cells and pose no risk of an immune reaction. Aspen Neuroscience starts with skin cells and repgrams them into induced pluripotent stem cells (iPSCs), then differentiates those into dopaminergic neuronal precursor cells. The cells are not only younger in terms of telomere lenghts, but have enhanced mitochondrial function. After transplantation, the neurons can reconstruct the lsot neural circuits in the patient. The therpay has received IND clearance and Fast Track designation from teh FDA.

Gene Therapy:

AskBio delivers the gene for glial-derive neurotrophic factor (GDNF) directly into the putamen, one of the brain regions damaged by Parkinson’s disease. Evidence from animal studies and postmortem brain examinations show that GDNF stimulates new terminal growth in neurons, boosting the ability of these neurons to make and process dopamine. The FDA has granted Fast Track Designation to this therapy called AB-1005 and a Phase II, blinded study is recruting (NCT06285643)

MeiraGTx has a therapy called AAV-AGD which uses an AAV capsid to deliver the gene for glutamic acid decarboxylase (GAD) to STN neurons, enabling them to produce GABA. The dopamine deficit in Parkinson’s disease causes hyperactivation of a brain region called the subthalamic nucleus (STN), which also contributes to motor symptoms. The neurotransmitter y-aminobutryic acid (GABA) can reduce STN hyperactivation and less then symptoms.

Voyager Therapeutics has developed a novel gene therapy in which a GBA1 gene replacement payload is carried by an AAV capsid across the blood brain barrier, eliminating the need for surgery to delvier the payload. GBA1 encods a lysosomal enzyme called glucocerebrosidase (GCase). Full inactivation of GBA1 causes Gaucher’s disease, a lysosomal storage disease and mutations in GBA1 are also found in around 10% of Parkinson’s disease patients. Gaucher’s disease can be treated with enzyme replacement therpay, which restores GCase function in the body, but becasue of the difficulty delivering large molecuels to the brain, this approach can not address neurological symptoms. Voyager’s capsid disclovery platform, TRACERapplies directed evolution to AAV capsids to find vectors optimized for dilivery to the brain and decreased dlivery to the liver. The AAV capsids take advantage of the brain’s natural mechanisms for transporting macromolcules across the blood brain barrier. Voyager has aprtnered with Neurocrine Biosciences to advance the GBA1 gene therapy.