Parkinson’s disease (PD) is characterized by motor deficits and a wide variety of non-motor symptoms. The age of onset, rate of disease progression and the precise profile of motor and non-motor symptoms display considerable individual variation. Neuropathologically, the loss of substantia nigra dopaminergic neurons is a key feature of PD. The vast majority of PD patients exhibit alpha-synuclein aggregates in several brain regions, but there is also great variability in the neuropathology between individuals. While the dopamine replacement therapies can reduce motor symptoms, current therapies do not modify the disease progression. Numerous clinical trials using a wide variety of approaches have failed to achieve disease modification. It has been suggested that the heterogeneity of PD is a major contributing factor to the failure of disease modification trials, and that it is unlikely that a single treatment will be effective in all patients. Precision medicine, using drugs designed to target the pathophysiology in a manner that is specific to each individual with PD, has been suggested as a way forward. PD patients can be stratified according to whether they carry one of the risk variants associated with elevated PD risk. In this review we assess current clinical trials targeting two enzymes, leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GBA), which are encoded by two most common PD risk genes. Because the details of the pathogenic processes coupled to the different LRRK2 and GBA risk variants are not fully understood, we ask if these precision medicine-based intervention strategies will prove “precise” or “personalized” enough to modify the disease process in PD patients. We also consider at what phases of the disease that such strategies might be effective, in light of the genes being primarily associated with the risk of developing disease in the first place, and less clearly linked to the rate of disease progression. Finally, we critically evaluate the notion that therapies targeting LRRK2 and GBA might be relevant to a wider segment of PD patients, beyond those that actually carry risk variants of these genes.
Parkinson’s disease (PD) is a progressive neurodegenerative disorder, potentially with several triggers and etiologies for the pathogenic processes that converge on the accumulation of misfolded α-synuclein (α-syn) in Lewy bodies and neurites [1] and the degeneration of dopamine (DA) neurons in the substantia nigra. These processes lead to the reduced striatal DA levels and debilitating motor disturbances as a consequence [2]. In addition to the classic motor symptoms, non-motor symptoms such as rapid-eye-movement sleep behavior disorder (RBD), hyposmia, pain, constipation, orthostatic hypotension and cognitive changes are common. Some of the non-motor symptoms may precede diagnosis by several years or even decades [3]. The annual economic expenditures associated with 630, 000 PD patients in the US in 2010 were estimated to be around $14.4 billion [4], and this expense is rapidly increasing given an anticipated prevalence to reach 1, 238, 000 cases in 2030 [5]. Therefore, developing disease-modifying treatments is of the utmost importance at present.
Symptomatic treatment of PD with, e.g., drugs targeting the dopamine system, has become increasingly “personalized” with multiple drugs and delivery systems being used according to the specific individual needs of each patient. However, when trying to achieve disease modification, a “precise” approach based on the molecular underpinnings of the disease in each patient, has not yet been fully tested. In 1–2% of PD cases, the cause of PD is attributed to the highly penetrant, autosomal dominant and recessive genes; in 5–10% of PD cases, PD is associated with strong risk genes (e.g. LRRK2 and GBA mutations); and the remaining cases are idiopathic without a single identifiable cause [6]. The risk of developing PD may also depend on the initial number of DA neurons that an individual was born with [7], the combined effect of risk genes [8, 9] and environmental factors (e.g. toxins, infections, and lifestyle diseases) [10], and the advancing age that constitutes the most significant risk factor [11]. The overall heritability of PD has been estimated at around 26–36% [12], indicating the importance of environmental factors and aging. Clinical features that occur during the prodromal phase of PD, before the onset of motor deficits, often include hyposmia, constipation and depression, which may provide clues to where the disease process starts. RBD is a condition strongly associated with PD, which is coupled to a > 80% risk of developing neurodegenerative synucleinopathy within 15 years after diagnosis of the sleep disorder and is present in 30% of those who exhibit PD symptoms [13, 14]. As the origins of PD are likely to be multifactorial, it may not be surprising that the disease widely varies in the age at diagnosis, the clinical symptom profile, the rate of progression and the neuropathological features [15]. Indeed, each PD patient is unique. While symptomatic treatment that relies on the replacement with striatal DA is initially effective for most patients, the idea that the disease progression be modified by treating PD patients according to a “one-size-fits-all” approach may be fundamentally flawed [16, 17].
Parkinson's Disease: Etiopathogenesis And Treatment
Several clinical trials have failed to demonstrate effective disease-modification in PD, and as mentioned above, the same disease pathway may not be relevant for all PD patients [16, 18, 19]. In addition, depending on the precise nature of the underlying pathogenic process the effective dosage of a treatment or the most relevant disease-stage might vary between individuals [15]. One reason, of many possible reasons (inappropriate target, poor target engagement, etc.), why putative disease-modifying treatments have failed in PD so far is that they might have been initiated too late. Thus, when the disease process has reached an advanced stage, it might be impossible to arrest the pathogenic cascade. Therefore, it seems attractive to initiate treatment with a potentially disease-modifying therapy during the prodromal stage, before the onset of motor symptoms [20]. Identifying patterns of biomarker change that are unique to subgroups of individuals who will further develop specific subtypes of PD would be imperative so as to identify the prodromal PD more accurately in the future [21, 22].
A “one-size-fits-only-one-or-a-few” approach considers that the pathogenic cascades involve different molecular pathways in different PD patients and suggests that the best way forward will be the precision medicine. According to the National Research Council Precision Medicine Initiative (launched in 2016), precision medicine is “An emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person” [23]. Precision medicine is preferred to the older term “personalized medicine” that may be misleading by suggesting that a treatment is designed entirely for a single person [23].
PD is a model candidate for precision medicine-based approaches. Clinical trials have been underway that target specific PD risk genes and their protein products [24]. In this review, we assess the current clinical drug trials targeting LRRK2 and GBA pathways in PD. We address some of the limitations of the selected disease-targets such as the considerable heterogeneity within PD patients with LRRK2 and GBA risk variants and propose how to interpret the present and the coming clinical data. Finally, we discuss if drugs that target LRRK2 and GBA can be relevant in idiopathic PD, where there is no evidence that the proteins encoded by these genes are directly perturbed.
Triggers, Facilitators, And Aggravators: Redefining Parkinson's Disease Pathogenesis: Trends In Neurosciences
LRRK2 is a large multifunctional and multidomain protein expressed particularly by immune cells (e.g. microglia and macrophages) and in tissues including kidney, lung and, to a much lower extent, brain [25]. It plays important roles in inflammation [25], DA receptor trafficking [26], synaptic vesicle endocytosis [27] and protein degradation among others [28]. Several variants in the LRRK2 gene have been associated with increased or decreased risk of PD, the autoimmune disorder Crohn’s disease, and the exacerbated immune response in leprosy [29, 30]. The most common G2019S variant accounts for up to 1% of sporadic and 4% of familial PD [31, 32, 33] and among Ashkenazi Jews as much as 10 and 28% respectively and in North African Arabs 36 and 39% respectively [34]. Other PD-associated LRRK2 variants include R1441G/C/H, Y1699C/G [35, 36], R1628P [37, 38], G2385R [39] and I2020T [40]. Some of these variants show varied penetrance depending on the ethnicity and where the individuals live, underlining that the genetic and environmental disease-modifiers remain to be identified. Current reports of the pathophysiological mechanism behind LRRK2-PD suggest a toxic gain-of-function mechanism generated from the increased kinase activity caused by variants in the MAPKKK domain (G2019S, I2020T) or indirectly by variants in the COR domain (Y1699C/G) or ROC domain (R1441G/C/H) that reduce the GTPase activity. The LRRK2 levels in the CSF are more increased in PD patients with the G2019S risk variant [41]. The rationale behind current drug trials aiming for LRRK2 inhibition in PD is principally based on this idea [42, 43] and also on a study reporting increased wild-type LRRK2 kinase activity in idiopathic PD [44]. It has been suggested that it is desirable to reduce elevated LRRK2 in neurons in PD, but the levels of LRRK2 expression are higher in immune cells in the brain and in peripheral organs [25]. This may indicate multiple prime disease mechanisms, of which one
Several clinical trials have failed to demonstrate effective disease-modification in PD, and as mentioned above, the same disease pathway may not be relevant for all PD patients [16, 18, 19]. In addition, depending on the precise nature of the underlying pathogenic process the effective dosage of a treatment or the most relevant disease-stage might vary between individuals [15]. One reason, of many possible reasons (inappropriate target, poor target engagement, etc.), why putative disease-modifying treatments have failed in PD so far is that they might have been initiated too late. Thus, when the disease process has reached an advanced stage, it might be impossible to arrest the pathogenic cascade. Therefore, it seems attractive to initiate treatment with a potentially disease-modifying therapy during the prodromal stage, before the onset of motor symptoms [20]. Identifying patterns of biomarker change that are unique to subgroups of individuals who will further develop specific subtypes of PD would be imperative so as to identify the prodromal PD more accurately in the future [21, 22].
A “one-size-fits-only-one-or-a-few” approach considers that the pathogenic cascades involve different molecular pathways in different PD patients and suggests that the best way forward will be the precision medicine. According to the National Research Council Precision Medicine Initiative (launched in 2016), precision medicine is “An emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person” [23]. Precision medicine is preferred to the older term “personalized medicine” that may be misleading by suggesting that a treatment is designed entirely for a single person [23].
PD is a model candidate for precision medicine-based approaches. Clinical trials have been underway that target specific PD risk genes and their protein products [24]. In this review, we assess the current clinical drug trials targeting LRRK2 and GBA pathways in PD. We address some of the limitations of the selected disease-targets such as the considerable heterogeneity within PD patients with LRRK2 and GBA risk variants and propose how to interpret the present and the coming clinical data. Finally, we discuss if drugs that target LRRK2 and GBA can be relevant in idiopathic PD, where there is no evidence that the proteins encoded by these genes are directly perturbed.
Triggers, Facilitators, And Aggravators: Redefining Parkinson's Disease Pathogenesis: Trends In Neurosciences
LRRK2 is a large multifunctional and multidomain protein expressed particularly by immune cells (e.g. microglia and macrophages) and in tissues including kidney, lung and, to a much lower extent, brain [25]. It plays important roles in inflammation [25], DA receptor trafficking [26], synaptic vesicle endocytosis [27] and protein degradation among others [28]. Several variants in the LRRK2 gene have been associated with increased or decreased risk of PD, the autoimmune disorder Crohn’s disease, and the exacerbated immune response in leprosy [29, 30]. The most common G2019S variant accounts for up to 1% of sporadic and 4% of familial PD [31, 32, 33] and among Ashkenazi Jews as much as 10 and 28% respectively and in North African Arabs 36 and 39% respectively [34]. Other PD-associated LRRK2 variants include R1441G/C/H, Y1699C/G [35, 36], R1628P [37, 38], G2385R [39] and I2020T [40]. Some of these variants show varied penetrance depending on the ethnicity and where the individuals live, underlining that the genetic and environmental disease-modifiers remain to be identified. Current reports of the pathophysiological mechanism behind LRRK2-PD suggest a toxic gain-of-function mechanism generated from the increased kinase activity caused by variants in the MAPKKK domain (G2019S, I2020T) or indirectly by variants in the COR domain (Y1699C/G) or ROC domain (R1441G/C/H) that reduce the GTPase activity. The LRRK2 levels in the CSF are more increased in PD patients with the G2019S risk variant [41]. The rationale behind current drug trials aiming for LRRK2 inhibition in PD is principally based on this idea [42, 43] and also on a study reporting increased wild-type LRRK2 kinase activity in idiopathic PD [44]. It has been suggested that it is desirable to reduce elevated LRRK2 in neurons in PD, but the levels of LRRK2 expression are higher in immune cells in the brain and in peripheral organs [25]. This may indicate multiple prime disease mechanisms, of which one
Several clinical trials have failed to demonstrate effective disease-modification in PD, and as mentioned above, the same disease pathway may not be relevant for all PD patients [16, 18, 19]. In addition, depending on the precise nature of the underlying pathogenic process the effective dosage of a treatment or the most relevant disease-stage might vary between individuals [15]. One reason, of many possible reasons (inappropriate target, poor target engagement, etc.), why putative disease-modifying treatments have failed in PD so far is that they might have been initiated too late. Thus, when the disease process has reached an advanced stage, it might be impossible to arrest the pathogenic cascade. Therefore, it seems attractive to initiate treatment with a potentially disease-modifying therapy during the prodromal stage, before the onset of motor symptoms [20]. Identifying patterns of biomarker change that are unique to subgroups of individuals who will further develop specific subtypes of PD would be imperative so as to identify the prodromal PD more accurately in the future [21, 22].
A “one-size-fits-only-one-or-a-few” approach considers that the pathogenic cascades involve different molecular pathways in different PD patients and suggests that the best way forward will be the precision medicine. According to the National Research Council Precision Medicine Initiative (launched in 2016), precision medicine is “An emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person” [23]. Precision medicine is preferred to the older term “personalized medicine” that may be misleading by suggesting that a treatment is designed entirely for a single person [23].
PD is a model candidate for precision medicine-based approaches. Clinical trials have been underway that target specific PD risk genes and their protein products [24]. In this review, we assess the current clinical drug trials targeting LRRK2 and GBA pathways in PD. We address some of the limitations of the selected disease-targets such as the considerable heterogeneity within PD patients with LRRK2 and GBA risk variants and propose how to interpret the present and the coming clinical data. Finally, we discuss if drugs that target LRRK2 and GBA can be relevant in idiopathic PD, where there is no evidence that the proteins encoded by these genes are directly perturbed.
Triggers, Facilitators, And Aggravators: Redefining Parkinson's Disease Pathogenesis: Trends In Neurosciences
LRRK2 is a large multifunctional and multidomain protein expressed particularly by immune cells (e.g. microglia and macrophages) and in tissues including kidney, lung and, to a much lower extent, brain [25]. It plays important roles in inflammation [25], DA receptor trafficking [26], synaptic vesicle endocytosis [27] and protein degradation among others [28]. Several variants in the LRRK2 gene have been associated with increased or decreased risk of PD, the autoimmune disorder Crohn’s disease, and the exacerbated immune response in leprosy [29, 30]. The most common G2019S variant accounts for up to 1% of sporadic and 4% of familial PD [31, 32, 33] and among Ashkenazi Jews as much as 10 and 28% respectively and in North African Arabs 36 and 39% respectively [34]. Other PD-associated LRRK2 variants include R1441G/C/H, Y1699C/G [35, 36], R1628P [37, 38], G2385R [39] and I2020T [40]. Some of these variants show varied penetrance depending on the ethnicity and where the individuals live, underlining that the genetic and environmental disease-modifiers remain to be identified. Current reports of the pathophysiological mechanism behind LRRK2-PD suggest a toxic gain-of-function mechanism generated from the increased kinase activity caused by variants in the MAPKKK domain (G2019S, I2020T) or indirectly by variants in the COR domain (Y1699C/G) or ROC domain (R1441G/C/H) that reduce the GTPase activity. The LRRK2 levels in the CSF are more increased in PD patients with the G2019S risk variant [41]. The rationale behind current drug trials aiming for LRRK2 inhibition in PD is principally based on this idea [42, 43] and also on a study reporting increased wild-type LRRK2 kinase activity in idiopathic PD [44]. It has been suggested that it is desirable to reduce elevated LRRK2 in neurons in PD, but the levels of LRRK2 expression are higher in immune cells in the brain and in peripheral organs [25]. This may indicate multiple prime disease mechanisms, of which one
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