Genetic susceptibility to caffeine intake and metabolism: a systematic review.

BACKGROUND: Coffee and tea consumption account for most caffeine intake and 2-3 billion cups are taken daily around the world. Caffeine dependence is a widespread but under recognized problem. OBJECTIVES: To conduct a systematic review on the genetic susceptibility factors affecting caffeine metabolism and caffeine reward and their association with caffeine intake. METHODOLOGY: We conducted PubMed and Embase searches using the terms "caffeine", "reward", "gene", "polymorphism", "addiction", "dependence" and "habit" from inception till 2024. The demographics, genetic and clinical data from included studies were extracted and analyzed. Only case-control studies on habitual caffeine drinkers with at least 100 in each arm were included. RESULTS: A total of 2552 studies were screened and 26 studies involving 1,851,428 individuals were included. Several genes that were involved with caffeine metabolism such as CYP1A2, ADORA2A, AHR, POR, ABCG2, CYP2A6, PDSS2 and HECTD4 rs2074356 (A allele specific to East Asians and monomorphic in Europeans, Africans and Americans) were associated with habitual caffeine consumption with effect size difference of 3% to 32% in number of cups of caffeinated drink per day per effect allele. In addition, ALDH2 was linked to the Japanese population. Genes associated with caffeine reward included BDNF, SLC6A4, GCKR, MLXIPL and dopaminergic genes such as DRD2 and DAT1 which had around 2-5% effect size difference in number of cups of caffeinated drink for each allele per day. CONCLUSION: Several genes that were involved in caffeine metabolism and reward were associated with up to 30% effect size difference in number of cups of caffeinated drink per day, and some associations were specific to certain ethnicities. Identification of at-risk caffeine dependence individuals can lead to early diagnosis and stratification of at-risk vulnerable individuals such as pregnant women and children, and can potentially lead to development of drug targets for dependence to caffeine.

[Effects of Nitrogen Addition on Soil Organic Carbon and Its Fractions in Karst Farmland and Forest Ecosystems of China Based on Meta-analysis].

In recent decades, with the intensification of human activities, atmospheric nitrogen （N） deposition has been increasing. N deposition affects carbon （C） cycling in terrestrial ecosystems, especially in fragile karst ecosystems. Karst ecosystems are considered to be an important C pool. To evaluate the impact of N deposition on soil organic C （SOC） and its fractions in karst ecosystems of China, we collected and collated 14 English literature published through the end of March 2023, yielding a total of 460 sets of experimental data. The meta-analysis examined the effect of N addition levels [low N: ≤50 kg·ï¼ˆhm2·a）-1, medium N: 50-100 kg·ï¼ˆhm2·a）-1, and high N: >100 kg·ï¼ˆhm2·a）-1, in terms of N] on SOC and its fractions [particular organic C （POC）, readily oxidized organic C （ROC）, microbial biomass C （MBC）, and dissolved organic C （DOC）]. The results showed that N addition levels significantly affected the responses of farmland and forest soil SOC and their active fractions to N addition. Specifically, low and high N additions significantly increased SOC concentration in farmland ecosystems, whereas medium N addition significantly increased SOC concentration in forest ecosystems. In addition, soil active C fraction concentrations increased under high N addition in farmland ecosystems and under low and medium N addition in forest ecosystems. Without considering the level of N addition, N addition significantly enhanced soil organic matter （SOM） mineralization in both farmland and forest ecosystems and increased the SOC concentration in farmland ecosystems but not forest ecosystems. The responses of different active C fractions to N addition were diverse. In farmland ecosystems, the POC and ROC concentrations increased, but DOC did not change with N addition. In forest ecosystems, the DOC and POC concentrations increased, but there was no significant effect on MBC. Moreover, the response ratios （RR） of SOC and its fractions in different ecosystems to N addition were influenced by different environmental factors. In farmland ecosystems, the response ratio of SOC was related to the annual average temperature and soil pH. The response ratio of DOC was affected by the annual average temperature, mean annual precipitation, and N addition rate. The POC response ratio was related to the N addition rate. In forest ecosystems, the effects of N addition on the SOC response ratio were significantly altered by the annual average temperature, mean annual precipitation, and soil pH. However, the response ratios of DOC, POC, and MBC were not affected by the annual average temperature, mean annual precipitation, soil pH, and N addition rate. Consequently, these findings indicate that N addition could enhance soil SOC concentration and promote soil C sequestration in farmland and forest ecosystems in karst regions, but this effect relies on the level of N addition. This provides a scientific basis for predicting the soil C sink function in karst ecosystems under climate change scenarios.

Interaction between caffeine consumption & genetic susceptibility in Parkinson's disease: A systematic review.

BACKGROUND: Caffeine is one of the most consumed psychoactive substances globally. Caffeine-gene interactions in Parkinson's disease (PD) has not been systematically examined. OBJECTIVES: To conduct a systematic review on the interaction between caffeine consumption and genetic susceptibility to PD. METHODOLOGY: We conducted PubMed and Embase search using terms "Genetic association studies", "Caffeine", "polymorphism" and "Parkinson's disease", from inception till 2023. Of the initial 2391 studies, 21 case-control studies were included. The demographic, genetic and clinical data were extracted and analyzed. RESULTS: We identified 21 studies which involved a total of 607,074 study subjects and 17 gene loci (SNCA, MAPT, HLA-DRA, NOS1, NOS3, GBA, ApoE, BST1, ESR2, NAT2, SLC2A13, LRRK2, NOS2A, GRIN2A, CYP1A2, ESR1, ADORA2A) have been investigated for the effect of gene-caffeine interaction and PD risk. The genes were identified through PD GWAS or involved in caffeine or related metabolism pathways. Based on the genetic association and interaction studies, only MAPT, SLC2A13, LRRK2, ApoE, NOS2A, GRIN2A, CYP1A2, and ADORA2A have been shown by at least one study to have a positive caffeine-gene interaction influencing the risk of PD. CONCLUSION: Studies have shown an interaction between caffeine with genetic variants of MAPT, SLC2A13, LRRK2, ApoE, NOS2A, GRIN2A, CYP1A2, and ADORA2A in modulating the risk of PD. Due to the potential limitations of these discovery/pilot studies, further independent replication studies are needed. Better designed genetic association studies in multi-ancestry and admixed cohorts to identify potential shared or unique multivariate gene-environmental interactions, as well as functional studies of gene-caffeine interactions will be useful.

Passive immunotherapy for Alzheimer's disease: challenges & future directions.

Passive immunotherapy with specific antibodies targeting Amyloid ß (Aß) peptide or tubulin-associated unit (tau) protein has emerged as a promising therapeutic approach in Alzheimer's disease (AD). However, in a recent phase III clinical study, Sperling et al. (N Engl J Med 10.1056/NEJMoa2305032, 2023) reported that solanezumab, a monoclonal antibody targeting Aß peptide, failed to slow cognitive decline in AD patients. Previously, three other anti-Aß antibodies, bapineuzumab, crenezumab, and gantenerumab, have also failed to show similar beneficial effects. In addition, three humanized antibodies targeting tau protein failed in their phase II trials. However, other anti-Aß antibodies, such as lecanemab (a humanized mAb binds to soluble Aß protofibrils), donanemab (a humanized mAb binds to insoluble, N-terminal truncated form of Aß peptides) and aducanumab (a human mAb binds to the aggregated form of Aß), have been shown to slow the decline of cognitive functions in early stage AD patients. The specific targets used in passive immunotherapy in these clinical trials may explain the divergent clinical outcomes. There are several challenges and limitations of passive immunotherapy using anti-Aß antibodies and long term longitudinal studies are needed to assess their efficacy, side effects and cost effectiveness in a wider spectrum of subjects, from pre-dementia to more advanced dementia. A combination therapeutic approach using both anti-Aß antibodies and other pharmaceutical agents should also be explored.

Tyrosine Hydroxylase Inhibitors and Dopamine Receptor Agonists Combination Therapy for Parkinson's Disease.

There are currently no disease-modifying therapies for Parkinson's disease (PD), a progressive neurodegenerative disorder associated with dopaminergic neuronal loss. There is increasing evidence that endogenous dopamine (DA) can be a pathological factor in neurodegeneration in PD. Tyrosine hydroxylase (TH) is the key rate-limiting enzyme for DA generation. Drugs that inhibit TH, such as alpha-methyltyrosine (α-MT), have recently been shown to protect against neurodegeneration in various PD models. DA receptor agonists can activate post-synaptic DA receptors to alleviate DA-deficiency-induced PD symptoms. However, DA receptor agonists have no therapeutic effects against neurodegeneration. Thus, a combination therapy with DA receptor agonists plus TH inhibitors may be an attractive therapeutic approach. TH inhibitors can protect and promote the survival of remaining dopaminergic neurons in PD patients' brains, whereas DA receptor agonists activate post-synaptic DA receptors to alleviate PD symptoms. Additionally, other PD drugs, such as N-acetylcysteine (NAC) and anticholinergic drugs, may be used as adjunctive medications to improve therapeutic effects. This multi-drug cocktail may represent a novel strategy to protect against progressive dopaminergic neurodegeneration and alleviate PD disease progression.

Reelin links Apolipoprotein E4, Tau, and Amyloid-ß in Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder that affects the cerebral cortex and hippocampus, and is characterised by progressive cognitive decline and memory loss. A recent report of a patient carrying a novel gain-of-function variant of RELN (H3447R, termed RELN-COLBOS) who developed resilience against presenilin-linked autosomal-dominant AD (ADAD) has generated enormous interest. The RELN-COLBOS variant enhances interactions with the apolipoprotein E receptor 2 (ApoER2) and very-low-density lipoprotein receptor (VLDLR), which are associated with delayed AD onset and progression. These findings were validated in a transgenic mouse model. Reelin is involved in neurodevelopment, neurogenesis, and neuronal plasticity. The evidence accumulated thus far has demonstrated that the Reelin pathway links apolipoprotein E4 (ApoE4), amyloid-ß (Aß), and tubulin-associated unit (Tau), which are key proteins that have been implicated in AD pathogenesis. Reelin and key components of the Reelin pathway have been highlighted as potential therapeutic targets and biomarkers for AD.

Genetic Association Studies in Restless Legs Syndrome: Risk Variants & Ethnic Differences.

BACKGROUND: Genetic association studies have not produced consistent results in restless legs syndrome (RLS). OBJECTIVES: To conduct a systematic review on genetic association studies in RLS to highlight the common gene variants and ethnic differences. METHODOLOGY: We conducted Pubmed, Embase, and Cochrane search using terms "Genetic association studies" and "restless legs syndrome" for candidate gene-based studies. Out of the initial 43 studies, 18 case control studies (from 2012 to 2022) were included. Thirteen studies including 10794 Caucasian subjects (4984 RLS cases and 5810 controls) and five studies involving 2009 Asian subjects (796 RLS cases and 1213 controls) were tabulated and analyzed. In addition, three Genome-Wide Association Studies (GWAS) in Asians and Europeans/Caucasians were included for comparisons. RESULTS: In the Asian population, gene variants in BST1, SNCA Rep1, IL1B, BTBD9, and MAP2K5/SKOR1 increased the risk of RLS (odds ratio range 1.2-2.8). In Caucasian populations, examples of variants that were associated with an increased risk of RLS (odds ratio range 1.1-1.9) include those in GABRR3 TOX3, ADH1B, HMOX1, GLO1, DCDC2C, BTBD9, SKOR1, and SETBP1. Based on the meta-analysis of GWAS studies, the rs9390170 variant in UTRN gene was identified to be a novel genetic marker for RLS in Asian cohorts, whereas rs113851554 in MEIS1 gene was a strong genetic factor among the >20 identified gene variants for RLS in Caucasian populations. CONCLUSION: Our systemic review demonstrates that multiple genetic variants modulate risk of RLS in Caucasians (such as MEIS1 BTBD9, MAP2K5) and in Asians (such as BTBD9, MAP2K5, and UTRN).

Neurodegenerative Diseases: Molecular Mechanisms and Therapies.

Neurodegenerative diseases are characterized by the progressive degeneration or death of neurons in the central or peripheral nervous system [...].

Role of dopamine in the pathophysiology of Parkinson's disease.

A pathological feature of Parkinson's disease (PD) is the progressive loss of dopaminergic neurons and decreased dopamine (DA) content in the substantia nigra pars compacta in PD brains. DA is the neurotransmitter of dopaminergic neurons. Accumulating evidence suggests that DA interacts with environmental and genetic factors to contribute to PD pathophysiology. Disturbances of DA synthesis, storage, transportation and metabolism have been shown to promote neurodegeneration of dopaminergic neurons in various PD models. DA is unstable and can undergo oxidation and metabolism to produce multiple reactive and toxic by-products, including reactive oxygen species, DA quinones, and 3,4-dihydroxyphenylacetaldehyde. Here we summarize and highlight recent discoveries on DA-linked pathophysiologic pathways, and discuss the potential protective and therapeutic strategies to mitigate the complications associated with DA.

Targeting gasdermin E in neurodegenerative diseases.

Neel et al. identified pathophysiologic clues linking gasdermin-E (GSDME) with frontotemporal dementia and amyotrophic lateral sclerosis.1 Therapeutic studies targeting GSDME may provide a viable approach for neurodegenerative diseases.

The role of tyrosine hydroxylase-dopamine pathway in Parkinson's disease pathogenesis.

BACKGROUND: Parkinson's disease (PD) is characterized by selective and progressive dopamine (DA) neuron loss in the substantia nigra and other brain regions, with the presence of Lewy body formation. Most PD cases are sporadic, whereas monogenic forms of PD have been linked to multiple genes, including Leucine kinase repeat 2 (LRRK2) and PTEN-induced kinase 1 (PINK1), two protein kinase genes involved in multiple signaling pathways. There is increasing evidence to suggest that endogenous DA and DA-dependent neurodegeneration have a pathophysiologic role in sporadic and familial PD. METHODS: We generated patient-derived dopaminergic neurons and human midbrain-like organoids (hMLOs), transgenic (TG) mouse and Drosophila models, expressing both mutant and wild-type (WT) LRRK2 and PINK1. Using these models, we examined the effect of LRRK2 and PINK1 on tyrosine hydroxylase (TH)-DA pathway. RESULTS: We demonstrated that PD-linked LRRK2 mutations were able to modulate TH-DA pathway, resulting in up-regulation of DA early in the disease which subsequently led to neurodegeneration. The LRRK2-induced DA toxicity and degeneration were abrogated by wild-type (WT) PINK1 (but not PINK1 mutations), and early treatment with a clinical-grade drug, α-methyl-L-tyrosine (α-MT), a TH inhibitor, was able to reverse the pathologies in human neurons and TG Drosophila models. We also identified opposing effects between LRRK2 and PINK1 on TH expression, suggesting that functional balance between these two genes may regulate the TH-DA pathway. CONCLUSIONS: Our findings highlight the vital role of the TH-DA pathway in PD pathogenesis. LRRK2 and PINK1 have opposing effects on the TH-DA pathway, and its balance affects DA neuron survival. LRRK2 or PINK1 mutations can disrupt this balance, promoting DA neuron demise. Our findings provide support for potential clinical trials using TH-DA pathway inhibitors in early or prodromic PD.

The APP intracellular domain promotes LRRK2 expression to enable feed-forward neurodegenerative mechanisms in Parkinson's disease.

Gain-of-function mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are common in familial forms of Parkinson's disease (PD), which is characterized by progressive neurodegeneration that impairs motor and cognitive function. We previously demonstrated that LRRK2-mediated phosphorylation of ß-amyloid precursor protein (APP) triggers the production and nuclear translocation of the APP intracellular domain (AICD). Here, we connected LRRK2 to AICD in a feed-forward cycle that enhanced LRRK2-mediated neurotoxicity. In cooperation with the transcription factor FOXO3a, AICD promoted LRRK2 expression, thus increasing the abundance of LRRK2 that promotes AICD activation. APP deficiency in LRRK2G2019S mice suppressed LRRK2 expression, LRRK2-mediated mitochondrial dysfunction, α-synuclein accumulation, and tyrosine hydroxylase (TH) loss in the brain, phenotypes associated with toxicity and loss of dopaminergic neurons in PD. Conversely, AICD overexpression increased LRRK2 expression and LRRK2-mediated neurotoxicity in LRRK2G2019S mice. In LRRK2G2019S mice or cultured dopaminergic neurons from LRRK2G2019S patients, treatment with itanapraced reduced LRRK2 expression and was neuroprotective. Itanapraced showed similar effects in a neurotoxin-induced PD mouse model, suggesting that inhibiting the AICD may also have therapeutic benefits in idiopathic PD. Our findings reveal a therapeutically targetable, feed-forward mechanism through which AICD promotes LRRK2-mediated neurotoxicity in PD.

Neurodegenerative diseases associated with non-coding CGG tandem repeat expansions.

Non-coding CGG repeat expansions cause multiple neurodegenerative disorders, including fragile X-associated tremor/ataxia syndrome, neuronal intranuclear inclusion disease, oculopharyngeal myopathy with leukodystrophy, and oculopharyngodistal myopathy. The underlying genetic causes of several of these diseases have been identified only in the past 2-3 years. These expansion disorders have substantial overlapping clinical, neuroimaging and histopathological features. The shared features suggest common mechanisms that could have implications for the development of therapies for this group of diseases - similar therapeutic strategies or drugs may be effective for various neurodegenerative disorders induced by non-coding CGG expansions. In this Review, we provide an overview of clinical and pathological features of these CGG repeat expansion diseases and consider the likely pathological mechanisms, including RNA toxicity, CGG repeat-associated non-AUG-initiated translation, protein aggregation and mitochondrial impairment. We then discuss future research needed to improve the identification and diagnosis of CGG repeat expansion diseases, to improve modelling of these diseases and to understand their pathogenesis. We also consider possible therapeutic strategies. Finally, we propose that CGG repeat expansion diseases may represent manifestations of a single underlying neuromyodegenerative syndrome in which different organs are affected to different extents depending on the gene location of the repeat expansion.

Altered striatal dopamine levels in Parkinson's disease VPS35 D620N mutant transgenic aged mice.

Vacuolar protein sorting 35 (VPS35) is a major component of the retromer complex that mediates the retrograde transport of cargo proteins from endosomes to the trans-Golgi network. Mutations such as D620N in the VPS35 gene have been identified in patients with autosomal dominant Parkinson's disease (PD). However, it remains poorly understood whether and how VPS35 deficiency or mutation contributes to PD pathogenesis; specifically, the studies that have examined VPS35 thus far have differed in results and methodologies. We generated a VPS35 D620N mouse model using a Rosa26-based transgene expression platform to allow expression in a spatial manner, so as to better address these discrepancies. Here, aged (20-months-old) mice were first subjected to behavioral tests. Subsequently, DAB staining analysis of substantia nigra (SN) dopaminergic neurons with the marker for tyrosine hydroxylase (TH) was performed. Next, HPLC was used to determine dopamine levels, along with levels of its two metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the striatum. Western blotting was also performed to study the levels of key proteins associated with PD. Lastly, autoradiography (ARG) evaluation of [3H]FE-PE2I binding to the striatal dopamine transporter DAT was carried out. We found that VPS35 D620N Tg mice displayed a significantly higher dopamine level than NTg counterparts. All results were then compared with that of current VPS35 studies to shed light on the disease pathogenesis. Our model allows future studies to explicitly control spatial expression of the transgene which would generate a more reliable PD phenotype.

Oxidized nicotinamide adenine dinucleotide-dependent mitochondrial deacetylase sirtuin-3 as a potential therapeutic target of Parkinson's disease.

Mitochondrial impairment is associated with progressive dopamine (DA) neuron degeneration in Parkinson's disease (PD). Recent findings highlight that Sirtuin-3 (SIRT3), a mitochondrial protein, is an oxidized nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase and a key modulator in maintaining integrity and functions of mitochondria. SIRT3 plays vital roles in regulation of mitochondrial functions, including mitochondrial ATP generation and energy metabolism, anti-oxidant defense, and cell death and proliferation. SIRT3 can deacetylate the transcriptional factors and crosstalk with different signaling pathways to cooperatively modulate mitochondrial functions and regulate defensive mitochondrial quality control (QC) systems. Down-regulated NAD+ level and decreased SIRT3 activity are related to aging process and has been pathologically linked to PD pathogenesis. Further, SIRT3 can bind and deacetylate PTEN-induced kinase 1 (PINK1) and PD protein 2 E3 ubiquitin protein ligase (Parkin) to facilitate mitophagy. Leucine Rich Repeat Kinase 2 (LRRK2)-G2019S mutation in PD is linked to SIRT3 impairment. Furthermore, SIRT3 is inversely associated with α-synuclein aggregation and DA neuron degeneration in PD. SIRT3 chemical activators and NAD+ precursors can up-regulate SIRT3 activity to protect against DA neuron degeneration in PD models. Taken together, SIRT3 is a promising PD therapeutic target and studies of SIRT3 functional modulators with neuroprotective capability will be of clinical interest.

The Therapeutic Implications of Tea Polyphenols Against Dopamine (DA) Neuron Degeneration in Parkinson's Disease (PD).

: Accumulative evidence indicated that the pathologically accumulated metal ions (iron species and Mn3+) and abnormally up-regulated monoamine oxidase B (MAOB) activity induced oxidation of endogenous dopamine (DA) can lead to mitochondria impairment, lysosome dysfunction, proteasome inhibition, and selective DA neuron vulnerability, which is implicated in the pathogenesis of Parkinson's disease (PD). The DA oxidation can generate deleterious reactive oxygen species (ROS) and highly reactive DA quinones (DAQ) to induce DA-related toxicity, which can be alleviated by DA oxidation suppressors, ROS scavengers, DAQ quenchers, and MAOB inhibitors. On the other hand, the nuclear factor erythroid 2-related factor 2 (Nrf2)-Keap1 and Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) anti-oxidative and proliferative signaling pathways play roles in anti-oxidative cell defense and mitochondria biogenesis, which is implicated in DA neuron protections. Therefore, agents with capabilities to suppress DA-related toxicity including inhibition of DA oxidation, scavenge of ROS, detoxification of DAQ, inhibition of MAOB, and modulations of anti-oxidative signaling pathways can be protective to DA neurons. Accumulative evidence shows that tea or coffee consumptions and smoking are related to deceased PD prevalence with unknown mechanisms. In this study, we investigate the protective capabilities of tea polyphenols and other PD relevant agents to inhibit DA-related toxicity and protect against environmental or genetic factors induced DA neuron degeneration in vitro and in vivo. We find that tea polyphenols can significantly suppress DA-related toxicity to protect DA neurons. The tea polyphenols can protect DA neurons via inhibition of DA oxidation, conjugation with DAQ, scavenge of ROS, inhibition of MAOB, and modulations of Nrf2-Keap1 and PGC-1α anti-oxidative signaling pathways. The tea polyphenols with more phenolic hydroxyl groups and ring structures have stronger protective functions. The protective capabilities of tea polyphenols is further strengthened by evidence that phenolic hydroxyl groups can directly conjugate with DAQ. However, GSH and other sulfhydyl groups containing agents have weaker capabilities to abrogate DA oxidation, detoxify ROS and DAQ and inhibit MAOB; whereas nicotine (NICO) and caffeine (CAF) can only modulate Nrf2-Keap1 and PGC-1α pathways to protect DA neurons weakly. The tea polyphenols are identified to protect against overexpression of mutant A30P α-synuclein (α-syn) induced DA neuron degeneration and PD-like symptoms in transgenic Drosophila. Based on achievements from current studies, the excellent and versatile protective capabilities of tea polyphenols are highlighted, which will contribute and benefit to future anti-PD therapy.

Molecular targets for modulating the protein translation vital to proteostasis and neuron degeneration in Parkinson's disease.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, which is characterized by the progressive loss of dopaminergic neurons in the Substantia Nigra pars compacta concomitant with Lewy body formation in affected brain areas. The detailed pathogenic mechanisms underlying the selective loss of dopaminergic neurons in PD are unclear, and no drugs or treatments have been developed to alleviate progressive dopaminergic neuron degeneration in PD. However, the formation of α-synuclein-positive protein aggregates in Lewy body has been identified as a common pathological feature of PD, possibly stemming from the consequence of protein misfolding and dysfunctional proteostasis. Proteostasis is the mechanism for maintaining protein homeostasis via modulation of protein translation, enhancement of chaperone capacity and the prompt clearance of misfolded protein by the ubiquitin proteasome system and autophagy. Deregulated protein translation and impaired capacities of chaperone or protein degradation can disturb proteostasis processes, leading to pathological protein aggregation and neurodegeneration in PD. In recent years, multiple molecular targets in the modulation of protein translation vital to proteostasis and dopaminergic neuron degeneration have been identified. The potential pathophysiological and therapeutic significance of these molecular targets to neurodegeneration in PD is highlighted.